2021/12/22 更新

写真a

カサイ トモナリ
笠井 智成
KASAI Tomonari
所属
中性子医療研究センター 准教授(特任)
職名
准教授(特任)
外部リンク

学位

  • 博士(農学) ( 岡山大学 )

研究分野

  • ライフサイエンス / 生体医工学

 

論文

  • Self-assembling A6K peptide nanotubes as a mercaptoundecahydrododecaborate (BSH) delivery system for boron neutron capture t (BNCT). 査読 国際誌

    Hiroyuki Michiue, Mizuki Kitamatsu, Asami Fukunaga, Nobushige Tsuboi, Atsushi Fujimura, Hiroaki Matsushita, Kazuyo Igawa, Tomonari Kasai, Natsuko Kondo, Hideki Matsui, Shuichi Furuya

    Journal of controlled release : official journal of the Controlled Release Society   330   788 - 796   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Boron neutron capture therapy (BNCT) is a tumor selective therapy, the effectiveness of which depends on sufficient 10B delivery to and accumulation in tumors. In this study, we used self-assembling A6K peptide nanotubes as boron carriers and prepared new boron agents by simple mixing of A6K and BSH. BSH has been used to treat malignant glioma patients in clinical trials and its drug safety and availability have been confirmed; however, its contribution to BNCT efficacy is low. A6K nanotube delivery improved two major limitations of BSH, including absence of intracellular transduction and non-specific drug delivery to tumor tissue. Varying the A6K peptide and BSH mixture ratio produced materials with different morphologies-determined by electron microscopy-and intracellular transduction efficiencies. We investigated the A6K/BSH 1:10 mixture ratio and found high intracellular boron uptake with no toxicity. Microscopy observation showed intracellular localization of A6K/BSH in the perinuclear region and endosome in human glioma cells. The intracellular boron concentration using A6K/BSH was almost 10 times higher than that of BSH. The systematic administration of A6K/BSH via mouse tail vein showed tumor specific accumulation in a mouse brain tumor model with immunohistochemistry and pharmacokinetic study. Neutron irradiation of glioma cells treated with A6K/BSH showed the inhibition of cell proliferation in a colony formation assay. Boron delivery using A6K peptide provides a unique and simple strategy for next generation BNCT drugs.

    DOI: 10.1016/j.jconrel.2020.11.001

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  • Deep Learning of Cancer Stem Cell Morphology Using Conditional Generative Adversarial Networks 査読

    Saori Aida, Junpei Okugawa, Serena Fujisaka, Tomonari Kasai, Hiroyuki Kameda, Tomoyasu Sugiyama

    Biomolecules   10 ( 6 )   931 - 931   2020年6月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:MDPI AG  

    Deep-learning workflows of microscopic image analysis are sufficient for handling the contextual variations because they employ biological samples and have numerous tasks. The use of well-defined annotated images is important for the workflow. Cancer stem cells (CSCs) are identified by specific cell markers. These CSCs were extensively characterized by the stem cell (SC)-like gene expression and proliferation mechanisms for the development of tumors. In contrast, the morphological characterization remains elusive. This study aims to investigate the segmentation of CSCs in phase contrast imaging using conditional generative adversarial networks (CGAN). Artificial intelligence (AI) was trained using fluorescence images of the Nanog-Green fluorescence protein, the expression of which was maintained in CSCs, and the phase contrast images. The AI model segmented the CSC region in the phase contrast image of the CSC cultures and tumor model. By selecting images for training, several values for measuring segmentation quality increased. Moreover, nucleus fluorescence overlaid-phase contrast was effective for increasing the values. We show the possibility of mapping CSC morphology to the condition of undifferentiation using deep-learning CGAN workflows.

    DOI: 10.3390/biom10060931

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  • Conditional Generative Adversarial Networks to Model iPSC-Derived Cancer Stem Cells 査読 国際誌

    Saori Aida, Hiroyuki Kameda, Sakae Nishisako, Tomonari Kasai, Atsushi Sato, Tomoyasu Sugiyama

    Journal of Advanced Computational Intelligence and Intelligent Informatics   24 ( 1 )   134 - 141   2020年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.20965/jaciii.2020.p0134

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  • A Novel Combination Cancer Therapy with Iron Chelator Targeting Cancer Stem Cells via Suppressing Stemness. 査読 国際誌

    Yuki Katsura, Toshiaki Ohara, Kazuhiro Noma, Takayuki Ninomiya, Hajime Kashima, Takuya Kato, Hiroaki Sato, Satoshi Komoto, Toru Narusaka, Yasuko Tomono, Boyi Xing, Yuehua Chen, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Tomonari Kasai, Masaharu Seno, Akihiro Matsukawa, Toshiyoshi Fujiwara

    Cancers   11 ( 2 )   2019年2月

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    記述言語:英語  

    Excess iron causes cancer and is thought to be related to carcinogenesis and cancer progression including stemness, but the details remain unclear. Here, we hypothesized that stemness in cancer is related to iron metabolism and that regulating iron metabolism in cancer stem cells (CSCs) may be a novel therapy. In this study, we used murine induced pluripotent stem cells that expressed specific stem cell genes such as Nanog, Oct3/4, Sox2, Klf4, and c-Myc, and two human cancer cell lines with similar stem cell gene expression. Deferasirox, an orally available iron chelator, suppressed expression of stemness markers and spherogenesis of cells with high stemness status in vitro. Combination therapy had a marked antitumor effect compared with deferasirox or cisplatin alone. Iron metabolism appears important for maintenance of stemness in CSCs. An iron chelator combined with chemotherapy may be a novel approach via suppressing stemness for CSC targeted therapy.

    DOI: 10.3390/cancers11020177

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  • Use of DNA-generated gold nanoparticles to radiosensitize and eradicate radioresistant glioma stem cells. 査読 国際誌

    Kunoh T, Shimura T, Kasai T, Matsumoto S, Mahmud H, Khayrani AC, Seno M, Kunoh H, Takada J

    Nanotechnology   30 ( 5 )   055101 - 055101   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1088/1361-6528/aaedd5

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  • Application of Conditional Generative Adversarial Nets to iPSC-Derived Cancer Stem Cell Modeling 査読

    Hiroyuki Kameda, Saori Aida, Sakae Nishisako, Tomonari Kasai, Atsushi Sato, Tomoyasu Sugiyama

    ISCIIA & ITCA 2018   2018年11月

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    記述言語:英語   掲載種別:研究論文(国際会議プロシーディングス)  

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  • Suppression effect on IFN-γ of adipose tissue-derived mesenchymal stem cells isolated from β2-microglobulin-deficient mice. 査読 国際誌

    Masuda J, Takayama E, Ichinohe T, Strober W, Mizuno-Kamiya M, Ikawa T, Kitani A, Kawaki H, Fuss I, Kawamoto H, Seno A, Vaidyanath A, Umemura N, Mizutani A, Kasai T, Honjo Y, Satoh A, Murakami H, Katsura Y, Kondoh N, Seno M

    Experimental and therapeutic medicine   16 ( 5 )   4277 - 4282   2018年11月

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    記述言語:英語  

    DOI: 10.3892/etm.2018.6689

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  • Deep-learning of cancer stem cell morphology for anti-cancer stem cell molecule screening 査読

    Sakae Nishisako, Saori Aida, Hiroyuki Kameda, Tomonari Kasai, Atsushi Sato, Tomoyasu Sugiyama

    Chem-Bio Informatics Society(CBI) Annual Meeting 2018   2018年10月

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    記述言語:英語  

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  • HSP-enriched properties of extracellular vesicles involve survival of metastatic oral cancer cells. 査読 国際誌

    Kisho Ono, Takanori Eguchi, Chiharu Sogawa, Stuart K Calderwood, Junya Futagawa, Tomonari Kasai, Masaharu Seno, Kuniaki Okamoto, Akira Sasaki, Ken-Ichi Kozaki

    Journal of cellular biochemistry   119 ( 9 )   7350 - 7362   2018年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cancer cells often secrete extracellular vesicles (EVs) that carry heat shock proteins (HSPs) with roles in tumor progression. Oral squamous cell carcinoma (OSCC) belongs to head and neck cancers (HNC) whose lymph-node-metastases often lead to poor prognosis. We have examined the EV proteome of OSCC cells and found abundant secretion of HSP90-enriched EVs in lymph-node-metastatic OSCC cells. Double knockdown of HSP90α and HSP90β, using small interfering RNA significantly reduced the survival of the metastatic OSCC cells, although single knockdown of each HSP90 was ineffective. Elevated expression of these HSP90 family members was found to correlate with poor prognosis of HNC cases. Thus, elevated HSP90 levels in secreted vesicles are potential prognostic biomarkers and therapeutic targets in metastatic OSCC.

    DOI: 10.1002/jcb.27039

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  • Up-Regulation of PI 3-Kinases and the Activation of PI3K-Akt Signaling Pathway in Cancer Stem-Like Cells Through DNA Hypomethylation Mediated by the Cancer Microenvironment. 査読 国際誌

    Aung Ko Ko Oo, Anna Sanchez Calle, Neha Nair, Hafizah Mahmud, Arun Vaidyanath, Junya Yamauchi, Aprilliana Cahya Khayrani, Juan Du, Md Jahangir Alam, Akimasa Seno, Akifumi Mizutani, Hiroshi Murakami, Yoshiaki Iwasaki, Ling Chen, Tomonari Kasai, Masaharu Seno

    Translational oncology   11 ( 3 )   653 - 663   2018年6月

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    記述言語:英語  

    Previously, we have succeeded in converting induced pluripotent stem cells (iPSCs) into cancer stem cells (CSCs) by treating the iPSCs with conditioned medium of Lewis lung carcinoma (LLC) cells. The converted CSCs, named miPS-LLCcm cells, exhibited the self-renewal, differentiation potential, and potential to form malignant tumors with metastasis. In this study, we further characterized miPS-LLCcm cells both in vivo and in vitro. The tumors formed by subcutaneous injection showed the structures with pathophysiological features consisting of undifferentiated and malignant phenotypes generally found in adenocarcinoma. Metastasis in the lung was also observed as nodule structures. Excising from the tumors, primary cultured cells from the tumor and the nodule showed self-renewal, differentiation potential as well as tumor forming ability, which are the essential characters of CSCs. We then characterized the epigenetic regulation occurring in the CSCs. By comparing the DNA methylation level of CG rich regions, the differentially methylated regions (DMRs) were evaluated in all stages of CSCs when compared with the parental iPSCs. In DMRs, hypomethylation was found superior to hypermethylation in the miPS-LLCcm cells and its derivatives. The hypo- and hypermethylated genes were used to nominate KEGG pathways related with CSC. As a result, several categories were defined in the KEGG pathways from which most related with cancers, significant and high expression of components was PI3K-AKT signaling pathway. Simultaneously, the AKT activation was also confirmed in the CSCs. The PI3K-Akt signaling pathway should be an important pathway for the CSCs established by the treatment with conditioned medium of LLC cells.

    DOI: 10.1016/j.tranon.2018.03.001

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  • Targeting Glioblastoma Cells Expressing CD44 with Liposomes Encapsulating Doxorubicin and Displaying Chlorotoxin-IgG Fc Fusion Protein. 査読 国際誌

    Hafizah Mahmud, Tomonari Kasai, Apriliana Cahya Khayrani, Mami Asakura, Aung Ko Ko Oo, Juan Du, Arun Vaidyanath, Samah El-Ghlban, Akifumi Mizutani, Akimasa Seno, Hiroshi Murakami, Junko Masuda, Masaharu Seno

    International journal of molecular sciences   19 ( 3 )   2018年2月

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    記述言語:英語  

    We recently have established a successful xenograft model of human glioblastoma cells by enriching hyaluronic acid-dependent spheroid-forming populations termed U251MG-P1 cells from U251MG cells. Since U251MG-P1 cells have been confirmed to express CD44 along with principal stemness marker genes, OCT3/4, SOX2, KLF4 and Nanog, this CD44 expressing population appeared to majorly consist of undifferentiated cells. Evaluating the sensitivity to anti-cancer agents, we found U251MG-P1 cells were sensitive to doxorubicin with IC50 at 200 nM. Although doxorubicin has serious side-effects, establishment of an efficient therapy targeting undifferentiated glioblastoma cell population is necessary. We previously designed a chlorotoxin peptide fused to human IgG Fc region without hinge sequence (M-CTX-Fc), which exhibited a stronger growth inhibitory effect on the glioblastoma cell line A172 than an original chlorotoxin peptide. Combining these results together, we designed M-CTX-Fc conjugated liposomes encapsulating doxorubicin and used U251MG-P1 cells as the target model in this study. The liposome modified with M-CTX-Fc was designed with a diameter of approximately 100-150 nm and showed high encapsulation efficiency, adequate loading capacity of anticancer drug, enhanced antitumor effects demonstrating increasing uptake into the cells in vitro; M-CTX-Fc-L-Dox shows great promise in its ability to suppress tumor growth in vivo and it could serve as a template for targeted delivery of other therapeutics.

    DOI: 10.3390/ijms19030659

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  • 異なる転移能を有する口腔扁平上皮癌細胞由来エクソソームに含まれるプロテオームの特性

    小野 喜章, 江口 傑徳, 十川 千春, 村上 純, 藤原 敏史, 笠井 智成, 妹尾 昌治, 佐々木 朗, 小崎 健一, 岡元 邦彰

    生命科学系学会合同年次大会   2017年度   [1LBA - 052]   2017年12月

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    記述言語:日本語   出版者・発行元:生命科学系学会合同年次大会運営事務局  

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  • Iron depletion is a novel therapeutic strategy to target cancer stem cells. 査読 国際誌

    Takayuki Ninomiya, Toshiaki Ohara, Kazuhiro Noma, Yuki Katsura, Ryoichi Katsube, Hajime Kashima, Takuya Kato, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki Kimura, Ling Chen, Tomonari Kasai, Masaharu Seno, Akihiro Matsukawa, Toshiyoshi Fujiwara

    Oncotarget   8 ( 58 )   98405 - 98416   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Adequate iron levels are essential for human health. However, iron overload can act as catalyst for the formation of free radicals, which may cause cancer. Cancer stem cells (CSCs), which maintain the hallmark stem cell characteristics of self-renewal and differentiation capacity, have been proposed as a driving force of tumorigenesis and metastases. In the present study, we investigated the role of iron in the proliferation and stemness of CSCs, using the miPS-LLCcm cell model. Although the anti-cancer agents fluorouracil and cisplatin suppressed the proliferation of miPS-LLCcm cells, these drugs did not alter the expression of stemness markers, including Nanog, SOX2, c-Myc, Oct3/4 and Klf4. In contrast, iron depletion by the iron chelators deferasirox and deferoxamine suppressed the proliferation of miPS-LLCcm cells and the expression of stemness markers. In an allograft model, deferasirox inhibited the growth of miPS-LLCcm implants, which was associated with decreased expression of Nanog and Sox2. Altogether, iron appears to be crucial for the proliferation and maintenance of stemness of CSCs, and iron depletion may be a novel therapeutic strategy to target CSCs.

    DOI: 10.18632/oncotarget.21846

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  • Practical Liposomal Formulation for Taxanes with Polyethoxylated Castor Oil and Ethanol with Complete Encapsulation Efficiency and High Loading Efficiency 査読

    Tsukasa Shigehiro, Junko Masuda, Shoki Saito, Apriliana C. Khayrani, Kazumasa Jinno, Akimasa Seno, Arun Vaidyanath, Akifumi Mizutani, Tomonari Kasai, Hiroshi Murakami, Ayano Satoh, Tetsuya Ito, Hiroki Hamada, Yuhki Seno, Tadakatsu Mandai, Masaharu Seno

    NANOMATERIALS   7 ( 10 )   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MDPI AG  

    Taxanes including paclitaxel and docetaxel are effective anticancer agents preferably sufficient for liposomal drug delivery. However, the encapsulation of these drugs with effective amounts into conventional liposomes is difficult due to their high hydrophobicity. Therefore, an effective encapsulation strategy for liposomal taxanes has been eagerly anticipated. In this study, the mixture of polyethoxylated castor oil (Cremophor EL) and ethanol containing phosphate buffered saline termed as CEP was employed as a solvent of the inner hydrophilic core of liposomes where taxanes should be incorporated. Docetaxel-, paclitaxel-, or 7-oxacetylglycosylated paclitaxel-encapsulating liposomes were successfully prepared with almost 100% of encapsulation efficiency and 29.9, 15.4, or 29.1 mol% of loading efficiency, respectively. We then applied the docetaxel-encapsulating liposomes for targeted drug delivery. Docetaxel-encapsulating liposomes were successfully developed HER2-targeted drug delivery by coupling HER2-specific binding peptide on liposome surface. The HER2-targeting liposomes exhibited HER2-specific internalization and enhanced anticancer activity in vitro. Therefore, we propose the sophisticated preparation of liposomal taxanes using CEP as a promising formulation for effective cancer therapies.

    DOI: 10.3390/nano7100290

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  • 舌癌細胞株由来エクソソーム解析による頸部リンパ節転移マーカーの探索

    小野 喜章, 江口 傑徳, 十川 千春, 村上 純, 笠井 智成, 妹尾 昌治, 佐々木 朗, 小崎 健一

    日本癌学会総会記事   76回   J - 1062   2017年9月

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    記述言語:英語   出版者・発行元:(一社)日本癌学会  

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  • A cancer stem cell model as the point of origin of cancerassociated fibroblasts in tumor microenvironment 査読

    Neha Nair, Anna Sanchez Calle, Maram Hussein Zahra, Marta Prieto-Vila, Aung Ko Ko Oo, Laura Hurley, Arun Vaidyanath, Akimasa Seno, Junko Masuda, Yoshiaki Iwasaki, Hiromi Tanaka, Tomonari Kasai, Masaharu Seno

    SCIENTIFIC REPORTS   7 ( 1 )   6838   2017年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Cancer-associated fibroblasts (CAFs) are one of the most prominent cell types in the stromal compartment of the tumor microenvironment. CAFs support multiple aspects of cancer progression, including tumor initiation, invasion, and metastasis. The heterogeneous nature of the stromal microenvironment is attributed to the multiple sources from which the cells in this compartment originate. The present study provides the first evidence that cancer stem cells (CSCs) are one of the key sources of CAFs in the tumor niche. We generated CSC-like cells by treating mouse induced pluripotent stem cells with conditioned medium from breast cancer cell lines. The resulting cell population expressed both CSC and pluripotency markers, and the sphere-forming CSC-like cells formed subcutaneous tumors in nude mice. Intriguingly, these CSC-like cells always formed heterogeneous populations surrounded by myofibroblast-like cells. Based on this observation, we hypothesized that CSCs could be the source of the CAFs that support tumor maintenance and survival. To address this hypothesis, we induced the differentiation of spheres and purified the myofibroblast-like cells. The resulting cells exhibited a CAF-like phenotype, suggesting that they had differentiated into the subpopulations of cells that support CSC self-renewal. These findings provide novel insights into the dynamic interplay between various microenvironmental factors and CAFs in the CSC niche.

    DOI: 10.1038/s41598-017-07144-5

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  • Anticancer effects of novel thalidomide analogs in A549 cells through inhibition of vascular endothelial growth factor and matrix metalloproteinase-2 査読

    Bishoy El-Aarag, Tomonari Kasai, Junko Masuda, Hussein Agwa, Magdy Zahran, Masaharu Seno

    BIOMEDICINE & PHARMACOTHERAPY   85   549 - 555   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER  

    Lung cancer is one of the major causes of cancer-related mortality worldwide, and non-small-cell lung cancer is the most common form of lung cancer. Several studies had shown that thalidomide has potential for prevention and therapy of cancer. Therefore, the current study aimed to investigate the antitumor effects of two novel thalidomide analogs in human lung cancer A549 cells. The antiproliferative, antimigratory, and apoptotic effects in A549 cells induced by thalidomide analogs were examined. In addition, their effects on the expression of mRNAs encoding vascular endothelial growth factor165 (VEGF165) and matrix metalloproteinase-2 (MMP-2) were evaluated. Their influence on the tumor volume in nude mice was also determined. Results revealed that thalidomide analogs exhibited antiproliferative, antimigratory, and apoptotic activities with more pronounced effect than thalidomide drug. Furthermore, analogs 1 and 2 suppressed the expression levels of VEGF165 by 42% and 53.2% and those of MMP-2 by 45% and 52%, respectively. Thalidomide analogs 1 and 2 also reduced the tumor volume by 30.11% and 53.52%, respectively. Therefore, this study provides evidence that thalidomide analogs may serve as a new therapeutic option for treating lung cancer. (C) 2016 Elsevier Masson SAS. All rights reserved.

    DOI: 10.1016/j.biopha.2016.11.063

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  • Hyaluronic Acid Mediated Enrichment of CD44 Expressing Glioblastoma Stem Cells in U251MG Xenograft Mouse Model 査読

    Arun Vaidyanath, Hafizah Binti Mahmud, Apriliana Cahya Khayrani, Aung KoKo Oo, Akimasa Seno, Mami Asakura, Tomonari Kasai, Masaharu Seno

    Journal of Stem Cell Research & Therapy   07 ( 04 )   2017年

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    出版者・発行元:{OMICS} Publishing Group  

    DOI: 10.4172/2157-7633.1000384

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  • Transient Tcf3 Gene Repression by TALE-Transcription Factor Targeting 査読

    Junko Masuda, Hiroshi Kawamoto, Warren Strober, Eiji Takayama, Akifumi Mizutani, Hiroshi Murakami, Tomokatsu Ikawa, Atsushi Kitani, Narumi Maeno, Tsukasa Shigehiro, Ayano Satoh, Akimasa Seno, Vaidyanath Arun, Tomonari Kasai, Ivan J. Fuss, Yoshimoto Katsura, Masaharu Seno

    APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY   180 ( 8 )   1559 - 1573   2016年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:HUMANA PRESS INC  

    Transplantation of hematopoietic stem and progenitor cells (HSCs) i.e., self-renewing cells that retain multipotentiality, is now a widely performed therapy for many hematopoietic diseases. However, these cells are present in low number and are subject to replicative senescence after extraction; thus, the acquisition of sufficient numbers of cells for transplantation requires donors able to provide repetitive blood samples and/or methods of expanding cell numbers without disturbing cell multipotentiality. Previous studies have shown that HSCs maintain their multipotentiality and self-renewal activity if TCF3 transcription function is blocked under B cell differentiating conditions. Taking advantage of this finding to devise a new approach to HSC expansion in vitro, we constructed an episomal expression vector that specifically targets and transiently represses the TCF3 gene. This consisted of a vector encoding a transcription activator-like effector (TALE) fused to a Kruppel-associated box (KRAB) repressor. We showed that this TALE-KRAB vector repressed expression of an exogenous reporter gene in HEK293 and COS-7 cell lines and, more importantly, efficiently repressed endogenous TCF3 in a human B lymphoma cell line. These findings suggest that this vector can be used to maintain multipotentiality in HSC being subjected to a long-term expansion regimen prior to transplantation.

    DOI: 10.1007/s12010-016-2187-4

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  • Characterization of gene expression patterns among artificially developed cancer stem cells using spherical self-organizing map 査読

    Akimasa Seno, Tomonari Kasai, Masashi Ikeda, Arun Vaidyanath, Junko Masuda, Akifumi Mizutani, Hiroshi Murakami, Tetsuya Ishikawa, Masaharu Seno

    Cancer Informatics   15   163 - 178   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Libertas Academica Ltd.  

    We performed gene expression microarray analysis coupled with spherical self-organizing map (sSOM) for artificially developed cancer stem cells (CSCs). The CSCs were developed from human induced pluripotent stem cells (hiPSCs) with the conditioned media of cancer cell lines, whereas the CSCs were induced from primary cell culture of human cancer tissues with defined factors (OCT3/4, SOX2, and KLF4). These cells commonly expressed human embryonic stem cell (hESC)/hiPSC-specific genes (POU5F1, SOX2, NANOG, LIN28, and SALL4) at a level equivalent to those of control hiPSC 201B7. The sSOM with unsupervised method demonstrated that the CSCs could be divided into three groups based on their culture conditions and original cancer tissues. Furthermore, with supervised method, sSOM nominated TMED9, RNASE1, NGFR, ST3GAL1, TNS4, BTG2, SLC16A3, CD177, CES1, GDF15, STMN2, FAM20A, NPPB, CD99, MYL7, PRSS23, AHNAK, and LOC152573 genes commonly upregulating among the CSCs compared to hiPSC, suggesting the gene signature of the CSCs.

    DOI: 10.4137/CIN.S39839

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  • Synthesis and in vitro cancer cell growth inhibition evaluation of 11-amino-modified 5-Me-indolo[2,3-b]quinolines and their COMPARE analyses. 査読

    Okada M, Mei ZW, Hossain MI, Tominaga T, Takebayashi T, Murakami M, Yasuda M, Shigehiro T, Kasai T, Mizutani A, Murakami H, El Sayed, Iel T, Dan S, Yamori T, Seno M, Inokuchi T

    Med Chem Res   25 ( 5 )   879 - 892   2016年2月

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s00044-016-1508-z

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  • Evaluation of glycosylated docetaxel-encapsulated liposomes prepared by remote loading under solubility gradient 査読

    Tsukasa Shigehiro, Wenjia Zhai, Arun Vaidyanath, Junko Masuda, Akifumi Mizutani, Tomonari Kasai, Hiroshi Murakami, Hiroki Hamada, David S. Salomon, Katsuhiko Mikuni, Yuhki Seno, Tadakatsu Mandai, Masaharu Seno

    JOURNAL OF MICROENCAPSULATION   33 ( 2 )   172 - 182   2016年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:TAYLOR & FRANCIS LTD  

    Docetaxel comprises one of the most effective anti-cancer drugs despite of serious side effects. Liposomes encapsulation is practically feasible to deliver the drug. However, due to the significant hydrophobicity, docetaxel will be integrated into the lipid bilayer resulting in poor encapsulation capacity. Here, we evaluated a remote loading strategy using a solubility gradient made between the two solvents for 7-glucosyloxyacetyldocetaxel, which has enhanced water solubility of docetaxel with a coupled glucose moiety. Therefore, 7-glucosyloxyacetyldocetaxel was more effectively encapsulated into liposomes with 71.0% of encapsulation efficiency than docetaxel. While 7-glucosyloxyacetyldocetaxel exhibited 90.9% of tubulin stabilisation activity of docetaxel, 7-glucosyloxyacetyldocetaxel encapsulated in liposomes significantly inhibited the growth of tumour in vivo with side effects less than unencapsulated drug. Collectively, the encapsulation of 7-glucosyloxyacetyldocetaxel into liposomes by remote loading under the solubility gradient is considered to be a promising application to prepare practical drug delivery system.

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  • A new PDAC mouse model originated from iPSCs-converted pancreatic cancer stem cells (CSCcm) 査読

    Anna Sanchez Calle, Neha Nair, Aung KoKo Oo, Marta Prieto-Vila, Megumi Koga, Apriliana Cahya Khayrani, Maram Hussein, Laura Hurley, Arun Vaidyanath, Akimasa Seno, Yoshiaki Iwasaki, Malu Calle, Tomonari Kasai, Masaharu Seno

    AMERICAN JOURNAL OF CANCER RESEARCH   6 ( 12 )   2799 - 2815   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:E-CENTURY PUBLISHING CORP  

    Pancreatic ductal adenocarcinoma (PDAC) is the most representative form of pancreatic cancers. PDAC solid tumours are constituted of heterogeneous populations of cells including cancer stem cells (CSCs), differentiated cancer cells, desmoplastic stroma and immune cells. The identification and consequent isolation of pancreatic CSCs facilitated the generation of genetically engineered murine models. Nonetheless, the current models may not be representative for the spontaneous tumour occurrence. In the present study, we show the generation of a novel pancreatic iPSC-converted cancer stem cell lines (CSCcm) as a cutting-edge model for the study of PDAC. The CSCcm lines were achieved only by the influence of pancreatic cancer cell lines conditioned medium and were not subjected to any genetic manipulation. The xenografts tumours from CSCcm lines displayed histopathological features of ADM, PanIN and PDAC lesions. Further molecular characterization from RNA-sequencing analysis highlighted primary culture cell lines (1st CSCcm) as potential candidates to represent the pancreatic CSCs and indicated the establishment of the pancreatic cancer molecular pattern in their subsequent progenies 2nd CSCcm and 3rd CSCcm. In addition, preliminary RNA-seq SNPs analysis showed that the distinct CSCcm lines did not harbour single point mutations for the oncogene Kras codon 12 or 13. Therefore, PDAC-CSCcm model may provide new insights about the actual occurrence of the pancreatic cancer leading to develop different approaches to target CSCs and abrogate the progression of this fatidic disease.

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  • iPSC-derived cancer stem cells provide a model of tumor vasculature 査読

    Marta Prieto-Vila, Ting Yan, Anna Sanchez Calle, Neha Nair, Laura Hurley, Tomonari Kasai, Hiroki Kakuta, Junko Masuda, Hiroshi Murakami, Akifumi Mizutani, Masaharu Seno

    AMERICAN JOURNAL OF CANCER RESEARCH   6 ( 9 )   1906 - 1921   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:E-CENTURY PUBLISHING CORP  

    To grow beyond a size of approximately 1-2 mm(3), tumor cells activate many processes to develop blood vasculature. Growing evidences indicate that the formation of the tumor vascular network is very complex, and is not restricted to angiogenesis. Cancer cell-derived tumor vasculatures have been recently described. Among them, endothelial differentiation of tumor cells have been directly related to cancer stem cells, which are cells within a tumor that possess the capacity to self-renew, and to exhibit multipotential heterogeneous lineages of cancer cells. Vasculogenic mimicry has been described to be formed by cancer cells expressing stemness markers. Thus, cancer stem cells have been proposed to contribute to vasculogenic mimicry, though its relation is yet to be clarified. Here, we analyzed the tumor vasculature by using a model of mouse cancer stem cells, miPS-LLCcm cells, which we have previously established from mouse induced pluripotent stem cells and we introduced the DsRed gene in miPS-LLCcm to trace them in vivo. Various features of vasculature were evaluated in ovo, in vitro, and in vivo. The tumors formed in allograft nude mice exhibited angiogenesis in chick chorioallantoic membrane assay. In those tumors, along with penetrated host endothelial vessels, we detected endothelial differentiation from cancer stem cells and formation of vasculogenic mimicry. The angiogenic factors such as VEGF-A and FGF2 were expressed predominantly in the cancer stem cells subpopulation of miPS-LLCcm cells. Our results suggested that cancer stem cells play key roles in not only the recruitment of host endothelial vessels into tumor, but also in maturation of endothelial linage of cancer stem cell's progenies. Furthermore, the undifferentiated subpopulation of the miPS-LLCcm participates directly in the vasculogenic mimicry formation. Collectively, we show that miPS-LLCcm cells have advantages to further study tumor vasculature and to develop novel targeting strategies in the future.

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  • A Unique Procedure to Identify Cell Surface Markers Through a Spherical Self-Organizing Map Applied to DNA Microarray Analysis. 査読

    Sugii Y, Kasai T, Ikeda M, Vaidyanath A, Kumon K, Mizutani A, Seno A, Tokutaka H, Kudoh T, Seno M

    Biomarkers in cancer   8   17 - 23   2016年

  • 鉄コントロールによる新規がん幹細胞治療

    二宮 卓之, 大原 利章, 勝部 亮一, 賀島 肇, 加藤 卓也, 野間 和広, 田澤 大, 香川 俊輔, 水谷 昭文, 笠井 智成, 妹尾 昌治, 藤原 俊義

    日本癌学会総会記事   74回   IS4 - 6   2015年10月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • Spherical Self-Organizing Map Detects MYBL 1 As Candidate Gene for Triple-Negative Breast Cancer. 査読

    Ikeda M, Kumon K, Omoto K, Sugii Y, Mizutani A, Vaidyanath A, Kudoh T, Kasai T, Masuda S, Seno M

    Neurosci Biomed Eng   3 ( 2 )   94 - 101   2015年

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  • Bacteria: Prospective Savior in Battle against Cancer 査読

    Neha Nair, Tomonari Kasai, Masaharu Seno

    ANTICANCER RESEARCH   34 ( 11 )   6289 - 6296   2014年11月

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    記述言語:英語   出版者・発行元:INT INST ANTICANCER RESEARCH  

    Conventional anticancer therapies such as chemotherapy are losing their sheen in the battle against cancer. Therefore, strategies for treatment of cancer need to be constantly modified to fulfill the growing demands of alternative therapies. Several viral and non-viral vectors have been exploited for anticancer gene therapy. But over the years bacteria have been proven to be an important candidate for successful evasion of cancer. They serve as invaluable source of tumor-specific anticancer genes, toxins, polysaccharides for synthesis of nanodrugs and gene-delivery vectors. The current review assesses the role of important bacterial groups in different spheres of anti-cancer research.

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  • Characterization of cancer stem-like cells derived from mouse induced pluripotent stem cells transformed by tumor-derived exosomes/microvesicles 査読

    Ting Yan, Masuda Junko, Mizutani Akifumi, Chen Ling, Shigehiro Tsukasa, Matsuda Shuichi, Kasai Tomonari, Kudoh Takayuki, Murakami Hiroshi, Hendrix Mary J. C, Strizzi Luigi, Salomon David S, Fu Li, Seno Masaharu

    CANCER RESEARCH   74 ( 19 )   2014年10月

  • Cancer stem cells maintain a hierarchy of differentiation by creating their niche 査読

    Akifumi Mizutani, Shuichi Matsuda, Ting Yan, Marta Prieto-Vila, Ling Chen, Ayano Satoh, Tomonari Kasai, Junko Masuda, Takyuki Kudoh, Hiroshi Murakami, Li Fu, David S. Salomon, Masaharu Seno

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    記述言語:英語   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2014-3026

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  • Efficient Drug Delivery of Paclitaxel Glycoside: A Novel Solubility Gradient Encapsulation into Liposomes Coupled with Immunoliposomes Preparation 査読

    Tsukasa Shigehiro, Tomonari Kasai, Masaharu Murakami, Sreeja C. Sekhar, Yuki Tominaga, Masashi Okada, Takayuki Kudoh, Akifumi Mizutani, Hiroshi Murakami, David S. Salomon, Katsuhiko Mikuni, Tadakatsu Mandai, Hiroki Hamada, Masaharu Seno

    PLOS ONE   9 ( 9 )   e107976   2014年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Although the encapsulation of paclitaxel into liposomes has been extensively studied, its significant hydrophobic and uncharged character has generated substantial difficulties concerning its efficient encapsulation into the inner water core of liposomes. We found that a more hydrophilic paclitaxel molecule, 7-glucosyloxyacetylpaclitaxel, retained tubulin polymerization stabilization activity. The hydrophilic nature of 7-glucosyloxyacetylpaclitaxel allowed its efficient encapsulation into the inner water core of liposomes, which was successfully accomplished using a remote loading method with a solubility gradient between 40% ethylene glycol and Cremophor EL/ethanol in PBS. Trastuzumab was then conjugated onto the surface of liposomes as immunoliposomes to selectively target human epidermal growth factor receptor-2 (HER2)-overexpressing cancer cells. In vitro cytotoxicity assays revealed that the immunoliposomes enhanced the toxicity of 7-glucosyloxyacetylpaclitaxel in HER2-overexpressing cancer cells and showed more rapid suppression of cell growth. The immunoliposomes strongly inhibited the tumor growth of HT-29 cells xenografted in nude mice. Notably, mice survived when treated with the immunoliposomes formulation, even when administered at a lethal dose of 7glucosyloxyacetylpaclitaxel in vivo. This data successfully demonstrates immunoliposomes as a promising candidate for the efficient delivery of paclitaxel glycoside.

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  • In vitro anti-proliferative and anti-angiogenic activities of thalidomide dithiocarbamate analogs 査読

    Bishoy Y. A. El-Aarag, Tomonari Kasai, Magdy A. H. Zahran, Nadia I. Zakhary, Tsukasa Shigehiro, Sreeja C. Sekhar, Hussein S. Agwa, Akifumi Mizutani, Hiroshi Murakami, Hiroki Kakuta, Masaharu Seno

    INTERNATIONAL IMMUNOPHARMACOLOGY   21 ( 2 )   283 - 292   2014年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Inhibition of angiogenesis is currently perceived as a promising strategy in the treatment of cancer. The anti-angiogenicity of thalidomide has inspired a second wave of research on this teratogenic drug. The present study aimed to investigate the anti-proliferative and anti-angiogenic activities of two thalidomide dithiocarbamate analogs by studying their anti-proliferative effects on human umbilical vein endothelial cells (HUVECs) and MDA-MB-231 human breast cancer cell lines. Their action on the expression levels of IL-6, IL-8, TNF-alpha, VEGF(165), and MMP-2 was also assessed. Furthermore, their effect on angiogenesis was evaluated through wound healing, migration, tube formation, and nitric oxide (NO) assays. Results illustrated that the proliferation of HUVECs and MDA-MB-231 cells was not significantly affected by thalidomide at 625-100 mu M. Thalidomide failed to block angiogenesis at similar concentrations. By contrast, thalidomide dithiocarbamate analogs exhibited significant anti-proliferative action on HUVECs and MDA-MB-231 cells without causing cytotoxicity and also showed powerful anti-angiogenicity in wound healing, migration, tube formation, and NO assays. Thalidomide analogs 1 and 2 demonstrated more potent activity to suppress expression levels of IL-6, IL-8, TNF-alpha, VEGF(165), and MMP-2 than thalidomide. Analog 1 consistently, showed the highest potency and efficacy in all the assays. Taken together, our results support further development and evaluation of novel thalidomide analogs as antitumor and anti-angiogenic agents. (C) 2014 The Authors. Published by Elsevier B.V.

    DOI: 10.1016/j.intimp2014.05.007

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  • Cancer stem cells maintain a hierarchy of differentiation by creating their niche 査読

    Shuichi Matsuda, Ting Yan, Akifumi Mizutani, Tatsuyuki Sota, Yuki Hiramoto, Marta Prieto-Vila, Ling Chen, Ayano Satoh, Takayuki Kudoh, Tomonari Kasai, Hiroshi Murakami, Li Fu, David S. Salomon, Masaharu Seno

    INTERNATIONAL JOURNAL OF CANCER   135 ( 1 )   27 - 36   2014年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    The self-renewal and differentiation properties of cancer stem cells (CSCs) are regulated and maintained by the CSC niche. However, the mechanism of this maintenance, especially the maintenance contributed by differentiated cancer cells, remains to be fully elucidated. Recently, we have established a model of CSCs, miPS-LLCcm, from mouse induced pluripotent stem cells (miPSCs). In vitro cultured miPS-LLCcm cells were autonomously balanced with stem-like cells and differentiated cells including vascular endothelial cells. Under these conditions, the CSC properties appeared to be stable in the presence of the factor(s) secreted by the differentiated cells. The factor(s) activated Notch signaling and promoted self-renewal of CSCs. In addition, the secreted factor(s) appeared to regulate the differentiation lineage of CSCs. Our results indicate that the differentiated progenies of CSCs containing vascular endothelium play important roles for regulating the CSC's properties. Therefore, miPS-LLCcm cells create their own in vitro niche to maintain themselves in the hierarchy of differentiating CSCs.

    DOI: 10.1002/ijc.28648

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  • Mouse induced pluripotent stem cell microenvironment generates epithelial-mesenchymal transition in mouse Lewis lung cancer cells 査読

    Ling Chen, Akifumi Mizutani, Tomonari Kasai, Ting Yan, Guoliang Jin, Arun Vaidyanath, Bishoy Y. A. El-Aarag, Yixin Liu, Takayuki Kudoh, David S. Salomon, Li Fu, Masaharu Seno

    AMERICAN JOURNAL OF CANCER RESEARCH   4 ( 1 )   80 - U92   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:E-CENTURY PUBLISHING CORP  

    Induced pluripotent stem (iPS) cells may be a powerful tool in regenerative medicine, but their potential tumorigenicity is a significant challenge for the clinical use of iPS cells. Previously, we succeeded in converting miPS cells into cancer stem cells (CSCs) under the conditions of tumor microenvironment. Both stem cells and tumor cells are profoundly influenced by bi-directional communication with their respective microenvironment, which dictates cell fate determination and behavior. The microenvironment derived from iPS cells has not been well studied. In this paper, we have investigated the effects of secreted factors from Nanog-mouse iPS (miPS) cells on mouse Lewis lung cancer (LLC) cells that are found in the conditioned media. The results demonstrated that miPS cells secrete factors that can convert the epithelia phenotype of LLC cells to a mesenchymal phenotype, and that can promote tumorigenisity, migration and invasion. Furthermore, LLC cells that have been exposed to miPS conditioned medium became resistant to apoptosis. These various biological effects suggest that the miPS microenvironment contain factors that can promote an epithelial-mesenchymal transition (EMT) through an active Snail-MMP axis or by suppressing differentiation in LLC cells.

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  • Characterization of Cancer Stem-Like Cells Derived from Mouse Induced Pluripotent Stem Cells Transformed by Tumor-Derived Extracellular Vesicles 査読

    Ting Yan, Akifumi Mizutani, Ling Chen, Mai Takaki, Yuki Hiramoto, Shuichi Matsuda, Tsukasa Shigehiro, Tomonari Kasai, Takayuki Kudoh, Hiroshi Murakami, Junko Masuda, Mary J. C. Hendrix, Luigi Strizzi, David S. Salomon, Li Fu, Masaharu Seno

    JOURNAL OF CANCER   5 ( 7 )   572 - 584   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:IVYSPRING INT PUBL  

    Several studies have shown that cancer niche can perform an active role in the regulation of tumor cell maintenance and progression through extracellular vesicles-based intercellular communication. However, it has not been reported whether this vesicle-mediated communication affects the malignant transformation of normal stem cells/progenitors. We have previously reported that the conditioned medium derived from the mouse Lewis Lung Carcinoma (LLC) cell line can convert mouse induced pluripotent stem cells (miPSCs) into cancer stem cells (CSCs), indicating that normal stem cells when placed in an aberrant microenvironment can give rise to functionally active CSCs. Here, we focused on the contribution of tumor-derived extracellular vesicles (tEVs) that are secreted from LLC cells to induce the transformation of miPSCs into CSCs. We isolated tEVs from the conditioned medium of LLC cells, and then the differentiating miPSCs were exposed to tEVs for 4 weeks. The resultant tEV treated cells (miPS-LLCev) expressed Nanog and Oct3/4 proteins comparable to miPSCs. The frequency of sphere formation of the miPS-LLCev cells in suspension culture indicated that the self-renewal capacity of the miPS-LLCev cells was significant. When the miPS-LLCev cells were subcutaneously transplanted into Balb/c nude mice, malignant liposarcomas with extensive angiogenesis developed. miPS-LLCevPT and miPS-LLCevDT, the cells established from primary site and disseminated liposarcomas, respectively, showed their capacities to self-renew and differentiate into adipocytes and endothelial cells. Moreover, we confirmed the secondary liposarcoma development when these cells were transplanted. Taken together, these results indicate that miPS-LLCev cells possess CSC properties. Thus, our current study provides the first evidence that tEVs have the potential to induce CSC properties in normal tissue stem cells/progenitors.

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  • Chlorotoxin-Fc Fusion Inhibits Release of MMP-2 from Pancreatic Cancer Cells 査読

    Samah El-Ghlban, Tomonari Kasai, Tsukasa Shigehiro, Hong Xia Yin, Sreeja Sekhar, Mikiko Ida, Anna Sanchez, Akifumi Mizutani, Takayuki Kudoh, Hiroshi Murakami, Masaharu Seno

    BIOMED RESEARCH INTERNATIONAL   2014   152659   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:HINDAWI PUBLISHING CORPORATION  

    Chlorotoxin (CTX) is a 36-amino acid peptide derived from Leiurus quinquestriatus (scorpion) venom, which inhibits low-conductance chloride channels in colonic epithelial cells. It has been reported that CTX also binds to matrix metalloproteinase-2 (MMP-2), membrane type-1 MMP, and tissue inhibitor of metalloproteinase-2, as well as CLC-3 chloride ion channels and other proteins. Pancreatic cancer cells require the activation of MMP-2 during invasion and migration. In this study, the fusion protein was generated by joining the CTX peptide to the amino terminus of the human IgG-Fc domain without a hinge domain, the monomeric form of chlorotoxin (M-CTX-Fc). The resulting fusion protein was then used to target pancreatic cancer cells (PANC-1) in vitro. M-CTX-Fc decreased MMP-2 release into the media of PANC-1 cells in a dose-dependent manner. M-CTX-Fc internalization into PANC-1 cells was observed. When the cells were treated with chlorpromazine (CPZ), the internalization of the fusion protein was reduced, implicating a clathrin-dependent internalization mechanism of M-CTX-Fc in PANC-1 cells. Furthermore, M-CTX-Fc clearly exhibited the inhibition of the migration depending on the concentration, but human IgG, as negative control of Fc, was not affected. The M-CTX-Fc may be an effective instrument for targeting pancreatic cancer.

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  • Eosinophil cationic protein enhances stabilization of β-catenin during cardiomyocyte differentiation in P19CL6 embryonal carcinoma cells. 査読

    Jin G, Mizutani A, Fukuda T, Otani T, Yan T, Prieto Vila M, Murakami H, Kudoh T, Hirohata S, Kasai T, Salomon DS, Seno M

    Molecular biology reports   40 ( 4 )   3165 - 3171   2013年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s11033-012-2390-5

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  • Identification of Caveolin-1 as a Potential Causative Factor in the Generation of Trastuzumab Resistance in Breast Cancer Cells 査読

    Sreeja C. Sekhar, Tomonari Kasai, Ayano Satoh, Tsukasa Shigehiro, Akifumi Mizutani, Hiroshi Murakami, Bishoy Y. A. El-Aarag, David S. Salomon, Anna Massaguer, Rafael de Llorens, Masaharu Seno

    JOURNAL OF CANCER   4 ( 5 )   391 - 401   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:IVYSPRING INT PUBL  

    The oncogenic tyrosine kinase receptor ErbB2 is a prognostic factor and target for breast cancer therapeutics. In contrast with the other ErbB receptors, ErbB2 is hardly internalized by ligand induced mechanisms, indicating a prevalent surface expression. Elevated levels of ErbB2 in tumor cells are associated with its defective endocytosis and down regulation. Here we show that caveolin-1 expression in breast cancer derived SKBR-3 cells (SKBR-3/Cav-1) facilitates ligand induced ErbB2 endocytosis using an artificial peptide ligand EC-eGFP. Similarly, stimulation with humanized anti ErbB2 antibody Trastuzumab (Herceptin) was found to be internalized and co-localized with caveolin-1 in SKBR-3/Cav-1 cells. Internalized EC-eGFP and Trastuzumab in SKBR-3/Cav-1 cells were then delivered via caveolae to the caveolin-1 containing early endosomes. Consequently, attenuated Fc receptor mediated ADCC functions were observed when exposed to Trastuzumab and EC-Fc (EC-1 peptide conjugated to Fc part of human IgG). On the other hand, this caveolae dependent endocytic synergy was not observed in parental SKBR-3 cells. Therefore, caveolin-1 expression in breast cancer cells could be a predictive factor to estimate how cancer cells are likely to respond to Trastuzumab treatment.

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  • Eosinophil cationic protein enhances cardiomyocyte differentiation of P19CL6 embryonal carcinoma cells by stimulating the FGF receptor signaling pathway 査読

    Guoliang Jin, Akifumi Mizutani, Takayuki Fukuda, Ling Chen, Keisuke Nakanishi, Ting Yan, Takayuki Kudoh, Satoshi Hirohata, Tomonari Kasai, Hiroshi Murakami, David S. Salomon, Masaharu Seno

    GROWTH FACTORS   30 ( 5 )   344 - 355   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:INFORMA HEALTHCARE  

    We investigated the functional role of eosinophil cationic protein (ECP) in regulating cardiomyogenesis using mouse P19CL6 embryonic carcinoma cells. ECP was confirmed to accelerate the cardiomyocyte differentiation of P19CL6 cells by enhancing the rate and area size of beating of cardiomyocyte and by facilitating the expression of cardiomyocyte-specific genes, such as GATA4 and alpha-MHC. Since cardiomyocyte differentiation in vivo is considered to follow mesoderm induction, the induction of Brachyury, a marker of mesoderm, was assessed. Brachyury expression was found to be enhanced after the addition of ECP. This enhancement was due to the stimulation of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation by ECP. In this context, treatment with SU5402, an inhibitor of fibroblast growth factor (FGF) receptor 1, suppressed Brachyury expression, phosphorylation of ERK1/2, and cardiomyocyte differentiation induced by ECP. We concluded that ECP might induce mesoderm differentiation through FGF signaling pathway and enhance subsequent cardiomyocyte differentiation in concert with dimethyl sulfoxide in P19CL6 cells. ECP may be a novel factor for cardiomyocyte differentiation, which should be very useful to prepare adequate numbers of cardiomyocytes for therapeutic cell transplantation.

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  • A Model of Cancer Stem Cells Derived from Mouse Induced Pluripotent Stem Cells 査読

    Ling Chen, Tomonari Kasai, Yueguang Li, Yuh Sugii, Guoliang Jin, Masashi Okada, Arun Vaidyanath, Akifumi Mizutani, Ayano Satoh, Takayuki Kudoh, Mary J. C. Hendrix, David S. Salomon, Li Fu, Masaharu Seno

    PLOS ONE   7 ( 4 )   e33544   2012年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Cancer stem cells (CSCs) are capable of continuous proliferation and self-renewal and are proposed to play significant roles in oncogenesis, tumor growth, metastasis and cancer recurrence. CSCs are considered derived from normal stem cells affected by the tumor microenvironment although the mechanism of development is not clear yet. In 2007, Yamanaka's group succeeded in generating Nanog mouse induced pluripotent stem (miPS) cells, in which green fluorescent protein (GFP) has been inserted into the 5'-untranslated region of the Nanog gene. Usually, iPS cells, just like embryonic stem cells, are considered to be induced into progenitor cells, which differentiate into various normal phenotypes depending on the normal niche. We hypothesized that CSCs could be derived from Nanog miPS cells in the conditioned culture medium of cancer cell lines, which is a mimic of carcinoma microenvironment. As a result, the Nanog miPS cells treated with the conditioned medium of mouse Lewis lung carcinoma acquired characteristics of CSCs, in that they formed spheroids expressing GFP in suspension culture, and had a high tumorigenicity in Balb/c nude mice exhibiting angiogenesis in vivo. In addition, these iPS-derived CSCs had a capacity of self-renewal and expressed the marker genes, Nanog, Rex1, Eras, Esg1 and Cripto, associated with stem cell properties and an undifferentiated state. Thus we concluded that a model of CSCs was originally developed from miPS cells and proposed the conditioned culture medium of cancer cell lines might perform as niche for producing CSCs. The model of CSCs and the procedure of their establishment will help study the genetic alterations and the secreted factors in the tumor microenvironment which convert miPS cells to CSCs. Furthermore, the identification of potentially bona fide markers of CSCs, which will help the development of novel anti-cancer therapies, might be possible though the CSC model.

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  • The Conformational Polymorphism of the Green Fluorescent Protein 査読

    Haidong Tan, Yueguang Li, Ling Chen, Takayuki Kudoh, Tomonari Kasai, Masaharu Seno

    MOLECULAR BIOLOGY   46 ( 1 )   142 - 148   2012年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MAIK NAUKA/INTERPERIODICA/SPRINGER  

    Green fluorescent protein (GFPuv) has been widely used as a reporter fused to individual targeting sequences. However, its state in liquid and its effect on other proteins are still unclear. The conformational polymorphisms of glutathione-S-transferase-green fluorescent protein (GST-GFPuv), GFPuv and GST were analyzed by native polyacrylamide gel, indicating that GST was in many different states while GFPuv and GST-GFPuv were only in four and two slightly different states. Four different circular dichroism spectra were obtained from the GFPuv polymorphisms. The single molecular behavior of GST-GFPuv and GFPuv was also characterized by MALDI-TOF MS. Thus, we demonstrated that: (1) there might be four different structural polymorphisms for the native GFPuv; (2) GFPuv could reduce its partner's polymorphism as a fusion protein. Although GFPuv had many merits as a reporter, its unreliability was found in the study. DOI: 10.1134/S0026893311060045

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  • The conformational polymorphism of the green fluorescent protein. 査読

    Tan H, Li Y, Chen L, Kudoh T, Kasai T, Seno M

    Molekuliarnaia biologiia   46 ( 1 )   156 - 161   2012年1月

  • Chlorotoxin Fused to IgG-Fc Inhibits Glioblastoma Cell Motility via Receptor-Mediated Endocytosis. 査読

    Kasai T, Nakamura K, Vaidyanath A, Chen L, Sekhar S, El-Ghlban S, Okada M, Mizutani A, Kudoh T, Murakami H, Seno M

    Journal of drug delivery   2012   975763   2012年

  • Enhanced internalization of ErbB2 in SK-BR-3 cells with multivalent forms of an artificial ligand 査読

    Arun Vaidyanath, Toshihiro Hashizume, Tadahiro Nagaoka, Nao Takeyasu, Hitomi Satoh, Ling Chen, Jiyou Wang, Tomonari Kasai, Takayuki Kudoh, Ayano Satoh, Li Fu, Masaharu Seno

    JOURNAL OF CELLULAR AND MOLECULAR MEDICINE   15 ( 11 )   2525 - 2538   2011年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Targeting and down-regulation of ErbB2, a member of EGF receptor family, is regarded as one of the key aspect for cancer treatment because it is often overexpressed in breast and ovarian cancer cells. Although natural ligands for ErbB2 have not been found, unlike other ErbB receptors, EC-1, a 20-amino acid circular peptide, has been shown to bind to ErbB2 as an artificial ligand. Previously we showed EC-1 peptide did not induce the internalization of ErbB2 in SK-BR-3 cells. In this report, we designed divalent and multivalent forms of EC-1 peptide with the Fc portion of the human IgG and bionanocapsule modified with ZZ-tag on its surface to improve the interaction with ErbB2. These forms showed higher affinity to ErbB2 than that of EC-1 monomer. Furthermore, prominent endosomal accumulation of ErbB2 occurred in SK-BR-3 cells when stimulated with EC-Fc ligand multivalently displayed on the surface of the bionanocapsule, whereas SK-BR-3 cells as themselves displayed stringent mechanism against ErbB2 internalization without stimulation. The multivalent form of EC-1 peptide appeared to internalize ErbB2 more efficiently than divalent form did. This internalization was unaffected by the inhibition of clathrin association, but inhibited when the cholesterol was depleted which explained either caveolar or GPI-AP-early endocytic compartment (GEEC) pathway. Because of the lack of caveolin-1 expression, caveolar machinery may be lost in SK-BR-3 cell line. Therefore, it is suggested that the multivalent form of EC-1 induces the internalization of ErbB2 through the GEEC pathway.

    DOI: 10.1111/j.1582-4934.2011.01277.x

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  • Structural and Spatial Associations between Fe, O, and C in the Network Structure of the Leptothrix ochracea Sheath Surface 査読

    Tomoko Suzuki, Hideki Hashimoto, Hiromichi Ishihara, Tomonari Kasai, Hitoshi Kunoh, Jun Takada

    APPLIED AND ENVIRONMENTAL MICROBIOLOGY   77 ( 21 )   7873 - 7875   2011年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC MICROBIOLOGY  

    The structural and spatial associations of Fe with O and C in the outer coat fibers of the Leptothrix ochracea sheath were shown to be substantially similar to the stalk fibers of Gallionella ferruginea, i.e., a central C core, probably of bacterial origin, and aquatic Fe interacting with O at the surface of the core.

    DOI: 10.1128/AEM.06003-11

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  • Isolation of a Leptothrix Strain, OUMS1, from Ocherous Deposits in Groundwater 査読

    Michinori Sawayama, Tomoko Suzuki, Hideki Hashimoto, Tomonari Kasai, Mitsuaki Furutani, Naoyuki Miyata, Hitoshi Kunoh, Jun Takada

    CURRENT MICROBIOLOGY   63 ( 2 )   173 - 180   2011年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Leptothrix species in aquatic environments produce uniquely shaped hollow microtubules composed of aquatic inorganic and bacterium-derived organic hybrids. Our group termed this biologically derived iron oxide as "biogenous iron oxide (BIOX)". The artificial synthesis of most industrial iron oxides requires massive energy and is costly while BIOX from natural environments is energy and cost effective. The BIOX microtubules could potentially be used as novel industrial functional resources for catalysts, adsorbents and pigments, among others if effective and efficient applications are developed. For these purposes, a reproducible system to regulate bacteria and their BIOX productivity must be established to supply a sufficient amount of BIOX upon industrial demand. However, the bacterial species and the mechanism of BIOX microtubule formation are currently poorly understood. In this study, a novel Leptothrix sp. strain designated OUMS1 was successfully isolated from ocherous deposits in groundwater by testing various culture media and conditions. Morphological and physiological characters and elemental composition were compared with those of the known strain L. cholodnii SP-6 and the differences between these two strains were shown. The successful isolation of OUMS1 led us to establish a basic system to accumulate biological knowledge of Leptothrix and to promote the understanding of the mechanism of microtubule formation. Additional geochemical studies of the OUMS1-related microstructures are expected provide an attractive approach to study the broad industrial application of bacteria-derived iron oxides.

    DOI: 10.1007/s00284-011-9957-6

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  • Construction of a high-efficiency multi-site-directed mutagenesis 査読

    Haidong Tan, Yueguang Li, Ling Chen, Tomonari Kasai, Masaharu Seno

    AFRICAN JOURNAL OF BIOTECHNOLOGY   10 ( 3 )   449 - 452   2011年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC JOURNALS  

    Although site-directed mutagenesis has been used in many fields, it still has low rate of success and high cost because of low-yield target products. A modified method for multi-site-directed mutagenesis was developed with shifted primer design and cold-start polymerase chain reaction (PCR). The developed method was successfully applied to hexapeptide gene synthesis and recombinant enterokinase gene modification in the plasmids pET41a and pET24b-EK. The efficiency was pronounced at a 1:10 molar ratio of 7-base mutant products to 705-bp fragment products as control. Even in a 10-base substitution mutagenic PCR, a 1:50 molar ratio of mutant products to 705-bp fragment products was reached. Meanwhile, the quality of mutants was proved through the transformation efficiency and sequencing. This method was beneficial to prepare high-quality multibase mutagenesis and also implied that large-scale multibase mutagenesis was feasible, efficient, economical, and productive.

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  • Development of Paclitaxel Glycoside Liposomes Conjugated with Anti-CD44 Antibody Targeting Ovarian Cancer Cells

    Apriliana C. Khayrani, Hafizah Mahmud, Tomonari Kasai, Tsukasa Shigehiro, Aung Ko Ko Oo, Juan Du, Md. Jahangir Alam, Koji Hara, Hiroki Hamada, Yuhki Seno, Said M. Afify, Tadakatsu Mandai, Masaharu Seno

    CANCER SCIENCE   109   1097 - 1097   2018年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:WILEY  

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  • The significance of c-Kit protooncogene in iCSC-derived PDAC model

    Anna Sanchez Calle, Kenta Hoshikawa, Neha Nair, Marta Prieto-Vila, Arun Vaidyanath, Tomonari Kasai, Masaharu Seno

    CANCER RESEARCH   76   2016年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2016-1725

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  • Cancer stem cells as the novel origin of cancer-associated fibroblast-like cells

    Neha Nair, Arun Vaidyanath, Kenta Hoshikawa, Anna Sanchez Calle, Tomonari Kasai, Masaharu Seno

    CANCER RESEARCH   76   2016年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2016-LB-278

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  • Synthesis, Biological Evaluation, Docking and QSAR Studies of Some Novel Naphthalimide Dithiocarbamate Analogs as Antitumor and Anti-Inflammatory Agents.

    Zahra MH, Osman AMA, Agwa H, Nair N, Calle AS, Hurley L, Farag D, Kasai T, Seno M, Zahran M

    Medicinal Chemistry (Los Angeles)   6 ( 12 )   694 - 703   2016年

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  • がんモデル動物を用いた悪性度の違いによる全身免疫能変化の解析

    増田 潤子, 高山 英次, 佐藤 あやの, 守本 祐司, 本庶 仁子, 石塚 俊晶, 徳野 慎一, 青笹 季文, 光吉 俊二, 重廣 司, 前野 成実, 村上 宏, 笠井 智成, 水谷 昭文, Vaidyanath Arun, 妹尾 彬正, 川木 晴美, 神谷 真子[水野], 近藤 信夫, 一瀬 雅夫, 一戸 辰夫, 妹尾 昌治

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   88回・38回   [1P1079] - [1P1079]   2015年12月

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    記述言語:日本語   出版者・発行元:(公社)日本生化学会  

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  • Derivation of a model of cancer stem cell from human induced pluripotent stem cells

    Tomonari Kasai, Kenta Hoshikawa, Shuto Takejiri, Masashi Ikeda, Kazuki Kumon, Anna Sanchez Calle, Arun Vaidyanath, Akifumi Mizutani, Chen Ling, Masaharu Seno

    CANCER RESEARCH   75   2015年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2015-LB-144

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  • Iron control is a novel therapeutic target of cancer stem cells

    Takayuki Ninomiya, Toshiaki Ohara, Hajime Kashima, Ryoichi Katsube, Kazuhiro Noma, Yasuko Tomono, Akifumi Mizutani, Tomonari Kasai, Masaharu Seno, Shinji Kuroda, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuhiro Shirakawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   75   2015年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2015-4243

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  • Insight into Cancer Stem Cell Niche; Lessons from Cancer Stem Cell Models Generated In Vitro.

    MizutaniA, Yan T, Vaidyanath A, Masuda J, Seno A, Kasai T, Murakami H, Seno M

    Biology in Stem Cell Niche, Part of the series Stem Cell Biology and Regenerative Medicine   2015年

  • Anti-cancer activity of immunoliposomes encapsulated effective amount of glycosylated paclitaxel with novel loading strategy

    Tsukasa Shigehiro, Tomonari Kasai, Akifumi Mizutani, Hiroshi Murakami, Katsuhiko Mikuni, Tadakatsu Mandai, Hiroki Hamada, Masaharu Seno

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2014-4461

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  • 鉄コントロールによるがん幹細胞の新規治療法(Iron control is a potent novel therapeutic for cancer stem cells) 査読

    二宮 卓之, 大原 利章, 浦野 真一, 勝部 亮一, 野間 和広, 田澤 大, 香川 俊輔, 水谷 昭文, 笠井 智成, 妹尾 昌治, 藤原 俊義

    日本癌学会総会記事   73回   P - 1187   2014年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • Cancer stem cells converted from pluripotent stem cells and the cancerous niche.

    Kasai T, Chen L, Mizutani A, Kudoh T, Murakami H, Fu L, Seno M

    Journal of Stem cells & regenerative medicine   10 ( 1 )   2 - 7   2014年

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  • A Cancer Stem Cell Model, an insight into the conversion of induced pluripotent stem cells to cancer stem-like cells.

    Mizutani A, Chen L, Kasai T, Kudoh T, Murakami H, Fu L, Seno M

    Cancer Stem Cells   61 - 77   2014年

  • A novel remote loading method with solubility gradient to encapsulate effevtive amount of taxanes into liposomes.

    Tsukasa Shigehiro, Tomonari Kasai, Akifumi Mizutani, Hiroshi Murakami, Katsuhiko Mikuni, Tadakatsu Mandai, Hiroki Hamada, Masaharu Seno

    CANCER RESEARCH   73 ( 8 )   2013年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2013-LB-8

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  • 再生医療薬としての心筋分化促進因子ECP (特集 ライフイノベーションの未来戦略)

    水谷 昭文, 笠井 智成, 妹尾 昌治

    化學工業   64 ( 4 )   249 - 253   2013年4月

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    記述言語:日本語   出版者・発行元:小峰工業出版  

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  • マウスiPS細胞から作るがん幹細胞モデル

    笠井智成, 陳 凌, 工藤孝幸, 水谷昭文, 妹尾昌治

    細胞工学   32 ( 3 )   330 - 337   2013年

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  • Preparation and evaluation of glycosylated paclitaxel loaded in tastuzumab-immunoliposome

    Masaharu Murakami, Tomonari Kasai, Masashi Okada, Katsuhiko Mikuni, Naoyoshi Egashira, Masaharu Seno, Hiroki Hamada

    CANCER RESEARCH   72   2012年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2012-5700

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  • Development and characterization of cancer stem cell model from mouse iPS cells

    Ling Chen, Shuichi Matsuda, Tomonari Kasai, Yuh Sugii, Masashi Okada, Koichi Igarashi, Ayano Satoh, Takayuki Kudoh, Takayuki Kudoh, Li Fu, Masaharu Seno

    CANCER RESEARCH   72   2012年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2012-418

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  • Plasma membrane-localized transporter for aluminum in rice. 国際誌

    Jixing Xia, Naoki Yamaji, Tomonari Kasai, Jian Feng Ma

    Proceedings of the National Academy of Sciences of the United States of America   107 ( 43 )   18381 - 5   2010年10月

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    記述言語:英語  

    Aluminum (Al) is the most abundant metal in the Earth's crust, but its trivalent ionic form is highly toxic to all organisms at low concentrations. How Al enters cells has not been elucidated in any organisms. Herein, we report a transporter, Nrat1 (Nramp aluminum transporter 1), specific for trivalent Al ion in rice. Nrat1 belongs to the Nramp (natural resistance-associated macrophage protein) family, but shares a low similarity with other Nramp members. When expressed in yeast, Nrat1 transports trivalent Al ion, but not other divalent ions, such as manganese, iron, and cadmium, or the Al-citrate complex. Nrat1 is localized at the plasma membranes of all cells of root tips except epidermal cells. Knockout of Nrat1 resulted in decreased Al uptake, increased Al binding to cell wall, and enhanced Al sensitivity, but did not affect the tolerance to other metals. Expression of Nrat1 is up-regulated by Al in the roots and regulated by a C2H2 zinc finger transcription factor (ART1). We therefore concluded that Nrat1 is a plasma membrane-localized transporter for trivalent Al, which is required for a prior step of final Al detoxification through sequestration of Al into vacuoles.

    DOI: 10.1073/pnas.1004949107

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  • Pea extracellular Cu/Zn-superoxide dismutase responsive to signal molecules from a fungal pathogen 査読

    Tomonari Kasai, Tomoko Suzuki, Kozue Ono, Ken’ichi Ogawa, Yoshishige Inagaki, Yuki Ichinose, Kazuhiro Toyoda, Tomonori Shiraishi

    J Gen Plant Pathol   72 ( 5 )   265 - 272   2006年

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