Faculty Profiles - OKAMOTO Kuniaki

Papers - OKAMOTO Kuniaki

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Regulatory Roles of HSP90-Rich Extracellular Vesicles Reviewed

Takanori Eguchi, Kisho Ono, Kazumi Kawata, Kuniaki Okamoto, Stuart K. Calderwood

Heat Shock Proteins 3 - 17 2019

Depletion of choresterol lipid efflux pump ABCG1 triggers accumulation of exosomes and regression of tumors

Eguchi Takanori, Sogawa Chiharu, Namba Yuri, Okusha Yuka, Kawai Hotaka, Ono Kisho, Itagaki Mami, Murakami Jun, Ohyama Kazumi, Asaumi Junichi, Okamoto Kuniaki

Proceedings for Annual Meeting of The Japanese Pharmacological Society 92 2-YIA-26 2019

Language：Japanese Publisher：Japanese Pharmacological Society

The ATP-binding cassette transporter G1 (ABCG1) is a cholesterol lipid efflux pump whose role in tumor growth has been largely unknown. Our transcriptomics revealed that ABCG1 was powerfully expressed in rapidly metastatic, aggregative colon cancer cells, in all the ABC transporter family members. Coincidently, genetic amplification of ABCG1 is found in 10% to 35% of clinical samples of metastatic cancer cases. Expression of ABCG1 was further elevated in three-dimensional tumoroids (tumor organoids) within stemness-enhancing tumor milieu, whereas depletion of ABCG1 lowered cellular aggregation and tumoroid growth in vitro as well as hypoxia-inducible factor 1α in cancer cells around the central necrotic areas in tumors in vivo. Notably, depletion of ABCG1 triggered the intracellular accumulation of extracellular vesicles (EVs) and regression of tumoroids. Collectively, these data suggest that ABCG1 plays a crucial role in tumorigenesis in metastatic cancer and that depletion of ABCG1 triggers tumor regression with the accumulation of EVs, their derivatives and cargos, implicating a novel ABCG1-targeting therapeutic strategy by which redundant and toxic substances may be accumulated in tumors leading to their regression.

DOI： 10.1254/jpssuppl.92.0_2-yia-26

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Drug repositioning using three-dimensional, MMP9 promoter activity-based anticancer drug screening

Sogawa Chiharu, Eguchi Takanori, Okusha Yuka, Ohyama Kazumi, Ono Kisho, Sogawa Norio, Okamoto Kuniaki

Proceedings for Annual Meeting of The Japanese Pharmacological Society 92 1-P-096 2019

Language：Japanese Publisher：Japanese Pharmacological Society

Cancer is one of the most serious diseases all over the world, especially metastasis and drug resistance are leading causes of death. There is an urgent need to establish new strategies for drug discovery. Success in the drug discovery depends on the development of appropriate tumor models that correspond closely to native tumor situation. Matrix metalloproteinases (MMPs) represent the most prominent family of proteinases associated with tumorigenesis and are regulators of tumor milieu. The cancer stem cell model fits well with tumorigenesis, metastasis and drug resistance. We have shown that cancer cell aggregation led to hypoxic tumoroids with marked upregulation of reprogramming and stemness genes as increased cancer stem cell using a 3D culture system. In the present study, we established a novel MMP9 promoter-driven cell-based reporter system using a rapidly metastatic colon cancer cell in the 3D culture system that evaluates cancer stemness and invasiveness. We used a concept of drug repositioning-using known molecules for new indications. We selected several compounds with inhibition to both tumoroid formation and MMP9 promoter activity. One of the compounds inhibited primary tumor formation, invasion and metastasis.

DOI： 10.1254/jpssuppl.92.0_1-p-096

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破骨細胞分化を制御する新規Rabタンパク質の同定と機能解析

奥舎有加, 板垣まみ, 十川千春, 江口傑徳, 岡元邦彰

岡山歯学会雑誌 37 ( 2 ) 82 - 82 2018.12

Carcinogenic epithelial-mesenchymal transition initiated by oral cancer exosomes is inhibited by anti-EGFR antibody cetuximab. Reviewed International journal

Toshifumi Fujiwara, Takanori Eguchi, Chiharu Sogawa, Kisho Ono, Jun Murakami, Soichiro Ibaragi, Jun-Ichi Asaumi, Stuart K Calderwood, Kuniaki Okamoto, Ken-Ichi Kozaki

Oral oncology 86 251 - 257 2018.11

Language：English Publishing type：Research paper (scientific journal)

Overexpression and increased signaling from the epidermal growth factor receptor (EGFR) often changes oral squamous cell carcinoma (OSCC) and thus EGFR is frequently targeted molecularly by the therapeutic antibody cetuximab. We assessed the roles of OSCC-derived extracellular vesicles (EVs), including exosomes in the trafficking of cetuximab and in epithelial-mesenchymal transition (EMT) of epithelial cells. OSCC cells abundantly expressed EGFR, which was secreted from cells with OSCC-EVs upon EGF stimulations. The OSCC-EGFR-EVs were then able to enter into and transform epithelial cells leading to increased mesenchymal traits with increased vimentin and spindle-like shapes. EGF priming of OSCC cells further increased this EMT-initiating effect of the OSCC-EVs. The internalization and pro-EMT effects of the OSCC-EVs were largely blocked by cetuximab. Thus, OSCC-derived EVs transform normal epithelial cells into a mesenchymal phenotype and anti-EGFR therapeutic antibody cetuximab inhibits such a carcinogenic effect of the OSCC-EVs.

File： 71. Fujiwara (Oral Oncol).pdf

DOI： 10.1016/j.oraloncology.2018.09.030

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Depletion of Lipid Efflux Pump ABCG1 Triggers the Intracellular Accumulation of Extracellular Vesicles and Reduces Aggregation and Tumorigenesis of Metastatic Cancer Cells. Reviewed International journal

Namba Y, Sogawa C, Okusha Y, Kawai H, Itagaki M, Ono K, Murakami J, Aoyama E, Ohyama K, Asaumi JI, Takigawa M, Okamoto K, Calderwood SK, Kozaki KI, Eguchi T

Front Oncol. 8 376 - 376 2018.10

Language：English Publishing type：Research paper (scientific journal)

The ATP-binding cassette transporter G1 (ABCG1) is a cholesterol lipid efflux pump whose role in tumor growth has been largely unknown. Our transcriptomics revealed that ABCG1 was powerfully expressed in rapidly metastatic, aggregative colon cancer cells, in all the ABC transporter family members. Coincidently, genetic amplification of ABCG1 is found in 10-35% of clinical samples of metastatic cancer cases. Expression of ABCG1 was further elevated in three-dimensional tumoroids (tumor organoids) within stemness-enhancing tumor milieu, whereas depletion of ABCG1 lowered cellular aggregation and tumoroid growth in vitro as well as hypoxia-inducible factor 1α in cancer cells around the central necrotic areas in tumors in vivo. Notably, depletion of ABCG1 triggered the intracellular accumulation of extracellular vesicles (EVs) and regression of tumoroids. Collectively, these data suggest that ABCG1 plays a crucial role in tumorigenesis in metastatic cancer and that depletion of ABCG1 triggers tumor regression with the accumulation of EVs and their derivatives and cargos, implicating a novel ABCG1-targeting therapeutic strategy by which redundant and toxic substances may be accumulated in tumors leading to their regression.

File： 72. Namba (Frontiers in Oncol).pdf

DOI： 10.3389/fonc.2018.00376

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Anti-EGFR antibody cetuximab is secreted by oral squamous cell carcinoma and alters EGF-driven mesenchymal transition. Reviewed International journal

Toshifumi Fujiwara, Takanori Eguchi, Chiharu Sogawa, Kisho Ono, Jun Murakami, Soichiro Ibaragi, Jun-Ichi Asaumi, Kuniaki Okamoto, Stuart K Calderwood, Ken-Ichi Kozaki

Biochemical and biophysical research communications 503 ( 3 ) 1267 - 1272 2018.9

Language：English Publishing type：Research paper (scientific journal)

Genetic amplification, overexpression, and increased signaling from the epidermal growth factor receptor (EGFR) are often found in oral squamous cell carcinoma (OSCC) and thus EGFR is frequently targeted molecularly by the therapeutic antibody cetuximab. We assessed effects of cetuximab in control of EGF-driven malignant traits of OSCC cells. EGF stimulation promoted progression level of mesenchymal traits in OSCC cells, which were attenuated by cetuximab but incompletely. We pursued a potential mechanism underlying such incomplete attenuation of OSCC malignant traits. Cetuximab promoted secretion of EGFR-EVs by OSCC cells and failed to inhibit EGF-driven secretion of EGFR-EVs. Cetuximab was also found to be robustly secreted with the EGFR-EVs by the OSCC cells. Thus, EGF promotes the level of mesenchymal traits of OSCC cells and secretion of EGFR-EVs, which involve cetuximab resistance.

File： 69. Fujiwara (BBRC).pdf

DOI： 10.1016/j.bbrc.2018.07.035

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HSP-enriched properties of extracellular vesicles involve survival of metastatic oral cancer cells. Reviewed International journal

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 2018.9

Language：English Publishing type：Research paper (scientific journal)

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.

File： 68. Ono (J Cell Biochem).pdf

DOI： 10.1002/jcb.27039

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急速転移性癌細胞株由来細胞外小胞による破骨細胞分化および癌細胞浸潤の制御

板垣まみ, 十川千春, 奥舎有加, 江口傑徳, 小野喜章, 岡元邦彰

Journal of Oral Biosciences Supplement 2018 347 - 347 2018.9

破骨細胞分化を負に制御するRabタンパク質の同定

奥舎有加, 板垣まみ, 十川千春, 江口傑徳, 坂井詠子, 筑波隆幸, 岡元邦彰

Journal of Oral Biosciences Supplement 2018 219 - 219 2018.9

Rutaecarpine attenuates osteoclastogenesis by impairing macrophage colony stimulating factor and receptor activator of nuclear factor κ-B ligand-stimulated signalling pathways. Reviewed International journal

Yutaka Fukuma, Eiko Sakai, Shunsuke Komaki, Kazuhisa Nishishita, Kuniaki Okamoto, Takayuki Tsukuba

Clinical and experimental pharmacology & physiology 45 ( 8 ) 863 - 865 2018.8

Language：English

Rutaecarpine is a major alkaloid isolated from Evodia rutaecarpa. Here, we investigated the effects of rutaecarpine on osteoclast differentiation induced by macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor κ-B ligand (RANKL) in bone marrow-derived macrophages (BMMs). Treatment with rutaecarpine significantly inhibited osteoclastogenesis and prevented bone resorption of BMM-derived osteoclasts. Mechanistically, rutaecarpine decreased the protein level of nuclear factor of activated T cells cytoplasmic-1 (NFATc1) and the phosphorylation of other signalling pathways during the osteoclast differentiation. Thus, rutaecarpine may be useful as a therapeutic agent for the treatment of bone diseases.

DOI： 10.1111/1440-1681.12941

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Organoids with cancer stem cell-like properties secrete exosomes and HSP90 in a 3D nanoenvironment Reviewed

Takanori Eguchi, Chiharu Sogawa, Yuka Okusha, Kenta Uchibe, Ryosuke Iinuma, Kisho Ono, Keisuke Nakano, Jun Murakami, Manabu Itoh, Kazuya Arai, Toshifumi Fujiwara, Yuri Namba, Yoshiki Murata, Kazumi Ohyama, Manami Shimomura, Hirohiko Okamura, Masaharu Takigawa, Tetsuya Nakatsura, Ken-ichi Kozaki, Kuniaki Okamoto, Stuart K. Calderwood

PLoS ONE 13 ( 2 ) 2018.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Public Library of Science

Ability to form cellular aggregations such as tumorspheres and spheroids have been used as a morphological marker of malignant cancer cells and in particular cancer stem cells (CSC). However, the common definition of the types of cellular aggregation formed by cancer cells has not been available. We examined morphologies of 67 cell lines cultured on three dimensional morphology enhancing NanoCulture Plates (NCP) and classified the types of cellular aggregates that form. Among the 67 cell lines, 49 cell lines formed spheres or spheroids, 8 cell lines formed grape-like aggregation (GLA), 8 cell lines formed other types of aggregation, and 3 cell lines formed monolayer sheets. Seven GLA-forming cell lines were derived from adenocarcinoma among the 8 lines. A neuroendocrine adenocarcinoma cell line PC-3 formed asymmetric GLA with ductal structures on the NCPs and rapidly growing asymmetric tumors that metastasized to lymph nodes in immunocompromised mice. In contrast, another adenocarcinoma cell line DU-145 formed spheroids in vitro and spheroid-like tumors in vivo that did not metastasize to lymph nodes until day 50 after transplantation. Culture in the 3D nanoenvironment and in a defined stem cell medium enabled the neuroendocrine adenocarcinoma cells to form slowly growing large organoids that expressed multiple stem cell markers, neuroendocrine markers, intercellular adhesion molecules, and oncogenes in vitro. In contrast, the more commonly used 2D serum-contained environment reduced intercellular adhesion and induced mesenchymal transition and promoted rapid growth of the cells. In addition, the 3D stemness nanoenvironment promoted secretion of HSP90 and EpCAM-exosomes, a marker of CSC phenotype, from the neuroendocrine organoids. These findings indicate that the NCP-based 3D environment enables cells to form stem cell tumoroids with multipotency and model more accurately the in vivo tumor status at the levels of morphology and gene expression.

DOI： 10.1371/journal.pone.0191109

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Actin binding LIM 1 (abLIM1) negatively controls osteoclastogenesis by regulating cell migration and fusion. Reviewed International journal

Haruna Narahara, Eiko Sakai, Yu Yamaguchi, Shun Narahara, Mayumi Iwatake, Kuniaki Okamoto, Noriaki Yoshida, Takayuki Tsukuba

Journal of cellular physiology 234 ( 1 ) 486 - 499 2018.1

Language：English Publishing type：Research paper (scientific journal)

Actin binding LIM 1 (abLIM1) is a cytoskeletal actin-binding protein that has been implicated in interactions between actin filaments and cytoplasmic targets. Previous biochemical and cytochemical studies have shown that abLIM1 interacts and co-localizes with F-actin in the retina and muscle. However, whether abLIM1 regulates osteoclast differentiation has not yet been elucidated. In this study, we examined the role of abLIM1 in osteoclast differentiation and function. We found that abLIM1 expression was upregulated during receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation, and that a novel transcript of abLIM1 was exclusively expressed in osteoclasts. Overexpression of abLIM1 in the murine monocytic cell line, RAW-D suppressed osteoclast differentiation and decreased expression of several osteoclast-marker genes. By contrast, small interfering RNA-induced knockdown of abLIM1 enhanced the formation of multinucleated osteoclasts and markedly increased the expression of the osteoclast-marker genes. Mechanistically, abLIM1 regulated the localization of tubulin, migration, and fusion in osteoclasts. Thus, these results indicate that abLIM1 negatively controls osteoclast differentiation by regulating cell migration and fusion mediated via actin formation.

File： 65. Narahara(J Cell Physiol).pdf

DOI： 10.1002/jcp.26605

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Transcription factor EB (TFEB) influences invasion and migration in oral squamous cell carcinomas. Reviewed International journal

Sakamoto H, Yamashita K, Okamoto K, Kadowaki T, Umeda M, Tsukuba T

Oral Dis. 24 ( 5 ) 741 - 748 2018

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and plays an important role in various cancers. However, the function of TFEB in oral squamous cell carcinomas has not been examined. The aim of this study was to elucidate the role of TFEB in oral squamous cell carcinomas. MATERIALS AND METHODS: Expression levels of TFEB were examined in six different human oral squamous carcinoma cells: HSC2, HSC3, HSC4, SAS, OSC20, and SCC25. Knockdown of TFEB using small interfering RNA in HSC2 and HSC4 cells was performed. Cell morphology was observed by immunofluorescence microscopy. Cell proliferation, invasion, and adhesion were analyzed. RESULTS: Expression levels of TFEB were high in HSC2, moderate in HSC4 and SCC25, and low in HSC3 and OSC20 cells. Knockdown of TFEB did not affect proliferation of HSC2 and HSC4 cells, but did induced enlargement of lysosomes and endosomes in HSC4 cells. TFEB silencing reduced invasion and migration of these HSC cell squamous carcinoma cells; however, increased cell adhesion was also observed. CONCLUSION: TFEB knockdown reduces invasion and migration of cancer cells, likely through lysosomal regulation. Taken together, TFEB influences cell invasion and migration of oral squamous cell carcinomas.

File： 63. Sakamoto (Oral Dis).pdf

DOI： 10.1111/odi.12826

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Dihydroartemisinin represses osteoclastogenesis of bone marrow macrophages through reduced NFATc1 expression and impaired phosphorylation of IκBα. Reviewed

Shunsuke Komaki, Eiko Sakai, Yutaka Fukuma, Kazuhisa Nishishita, Kuniaki Okamoto, Takayuki Tsukuba

Biomedical research (Tokyo, Japan) 39 ( 4 ) 169 - 177 2018

Language：English Publishing type：Research paper (scientific journal)

Osteoclasts are multinucleated bone resorbing cells whose differentiation is regulated by several important signaling pathways. Several lines of evidence indicate that dihydroartemisinin (DHA), an anti-malarial drug, inhibits osteoclast differentiation with little cytotoxicity. However, the detailed inhibitory mechanisms of DHA on osteoclastogenesis from native cells remain to be elucidated. In this study, we investigated the effects of DHA on the differentiation of bone marrow-derived macrophages into osteoclasts. DHA inhibited receptor activator of nuclear factor κ-B ligand (RANKL)-induced osteoclast formation and its bone resorbing activity. Mechanistically, DHA treatment markedly abolished phosphorylation of IκBα, and slightly affected a p38 MAPK dependent pathway. Moreover, DHA treatment induced down-regulation of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), a master regulator for osteoclast differentiation and its target proteins, such as Src and cathepsin K. These results indicate that DHA represses RANKL-induced osteoclastogenesis of bone marrow macrophages through reduced NFATc1 expression and impaired phosphorylation of IκBα.

File： 70. Komaki (Biomed Res).pdf

DOI： 10.2220/biomedres.39.169

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The intranuclear PEX domain of MMP involves proliferation, migration, and metastasis of aggressive adenocarcinoma cells. Reviewed International journal

Okusha Y, Eguchi T, Sogawa C, Okui T, Nakano K, Okamoto K, Kozaki KI

J Cell Biochem. 119 ( 9 ) 7363 - 7376 2018

Language：English Publishing type：Research paper (scientific journal)

Members of matrix metalloproteinase (MMP) family promote cancer cell migration, invasion, and metastasis through alteration of the tumor milieu, intracellular signaling pathways, and transcription. We examined gene expression signatures of colon adenocarcinoma cell lines with different metastatic potentials and found that rapidly metastatic cells powerfully expressed genes encoding MMP3 and MMP9. The non-proteolytic PEX isoform and proteolytic isoforms of MMPs were significantly expressed in the metastatic cells in vitro. Knockdown of MMP3 attenuated cancer cell migration and invasion in vitro and lung metastasis in vivo. Profound nuclear localization of MMP3/PEX was found in tumor-stroma marginal area. In contrast, MMP9 was localized in central area of subcutaneous tumors. Overexpression of the PEX isoform of MMP3 promoted proliferation and migration of the rapidly metastatic cells in vitro. Taken together, the non-proteolytic PEX isoform of MMPs locating in cell nuclei involves proliferation, migration, and subsequent metastasis of aggressive adenocarcinoma cells.

File： 67. Okusha (J Cell Biochem).pdf

DOI： 10.1002/jcb.27040

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Rutaecarpine attenuates osteoclastogenesis by impairing M-CSF and RANKL-stimulated signaling pathways. Reviewed

Fukuma Y, Sakai E, Komaki S, Nishishita K, Okamoto K, Tsukuba T

Clin Exp Pharmacol Physiol. 2018