Faculty Profiles - SAKAGUCHI Masakiyo

MISC - SAKAGUCHI Masakiyo

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Mechanistic Analysis of Resistance to REIC/Dkk-3-induced Apoptosis in Human Bladder Cancer Cells

Tomoko Kobayashi, Masakiyo Sakaguchi, Ryuta Tanimoto, Fernando Abarzua, Mikiro Takaishi, Haruki Kaku, Ken Kataoka, Takashi Saika, Yasutomo Nasu, Masahiro Miyazaki, Hiromi Kumon, Nam-ho Huh

ACTA MEDICA OKAYAMA 62 ( 6 ) 393 - 401 2008.12

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

We have recently shown that a new therapeutic modality using the REIC/Dkk-3 gene (Ad-REIC) is effective against various human cancers, including those of prostate, testis and breast origins. The aim of the present study was to examine the sensitivity of bladder cancers to Ad-REIC and to clarify the molecular mechanisms that determine sensitivity/resistance. We found that 2 human bladder cancer cell lines, T24 and J82, are resistant to Ad-REIC. In T24 and J82 cells, the ER stress response and activation of JNK were observed in a manner similar to that in the sensitive PC3 cells. Translocation of Bax to mitochondria occurred in PC3 cells but not in T24 and J82 cells. Bcl-2 was remarkably overexpressed in T24 and J82 compared with the expression levels in sensitive cell lines. Treatment of T24 and J82 cells with a Bcl-2 inhibitor sensitized the cells to Ad-REIC-induced apoptosis. The results indicate that some human bladder cancers are resistant to apoptosis induced by overexpression of REIC/Dkk-3, which is at least in part due to up-regrulation of Bcl-2. These results provide a basis for possible use of Bcl-2 as a marker of sensitive cancers and to try to sensitize resistant cancers to Ad-REIC by down-regrulation of Bcl-2.

DOI： 10.18926/AMO/30945

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The structure of S100A11 fragment explains a local structural change induced by phosphorylation

Takahide Kouno, Mineyuki Mizuguchi, Masakiyo Sakaguchi, Eiichi Makino, Yoshihiro Mori, Hiroyuki Shinoda, Tomoyasu Aizawa, Makoto Demur, Nam-Ho Huh, Keiichi Kawano

JOURNAL OF PEPTIDE SCIENCE 14 ( 10 ) 1129 - 1138 2008.10

Language：English Publisher：JOHN WILEY & SONS LTD

S100A11 protein is a member of the S100 family containing two EF-hand motifs. It undergoes phophorylation on residue T10 after cell stimulation such as an increase in Ca2+ concentration. Phosphorylated S100A11 I can be recognized by its target protein, nucleolin. Although S100A11 is initially expressed in the cytoplasm, it is transported to the nucleus by the action of nucleolin. In the nucleus, S100A11 suppresses the growth of keratinocytes through p21(CIP1/WAF1) activation and induces cell differentiation. Interestingly, the N-terminal fragment of S100A11 has the same activity as the full-length protein: i.e. it is phosphorylated in vivo and binds to nucleolin. In addition, this fragment leads to the arrest of cultured keratinocyte growth. We examined the solution structure of this fragment peptide and explored its structural properties before and after phosphorylation. In a trifluoroethanol solution, the peptide adopts the alpha-helical structure just as the corresponding region of the full-length S100A11. Phosphorylation induces a disruption of the N-capping conformation of the alpha-helix, and has a tendency to perturb its surrounding structure. Therefore, the phosphorylated threonine lies in the N-terminal edge of the alpha-helix. This local structural change can reasonably explain why the phosphorylation of a residue that is initially buried in the interior of protein allows it to be recognized by the binding partner. Copyright (C) 2008 European Peptide Society and John Wiley & Sons, Ltd.

DOI： 10.1002/psc.1050

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Intracellular delivery of glutathione S-transferase-fused proteins into mammalian cells by polyethylenimine-glutathione conjugates

Hitoshi Murata, Junichiro Futami, Midori Kitazoe, Takayuki Yonehara, Hidetaka Nakanishi, Megumi Kosaka, Hiroko Tada, Masakiyo Sakaguchi, Yasuyuki Yagi, Masaharu Seno, Nam-ho Huh, Hidenori Yamada

JOURNAL OF BIOCHEMISTRY 144 ( 4 ) 447 - 455 2008.10

Language：English Publisher：OXFORD UNIV PRESS

The glutathione S-transferase (GST)-fused protein expression system has been extensively used to generate a large quantity of proteins and has served for functional analysis in vitro. In this study, we developed a novel approach for the efficient intracellular delivery of GST-fused proteins into living cells to expand their usefulness up to in vivo use. Since protein cationization techniques are powerful strategies for efficient intracellular uptake by adsorptive-mediated endocytosis, GST-fused proteins were cationized by forming a complex with a polycationic polyethylenimine (PEI)-glutathione conjugate. On screening of protein transduction, optimized PEI-glutathione conjugate for protein transduction was characterized by a partly oligomerized mixture of PEI with average molecular masses of 600 (PEI600) modified with multiple glutathiones, which could have sufficient avidity for GST. Furthermore, enhanced endosomal escape of transduced GST-fused proteins was observed when they were delivered with a glutathione-conjugated PEI600 derivative possessing a hydroxybutenyl moiety. These results were confirmed by both intracellular confocal imaging of GST-fused green fluorescent protein and activation of an endogenous growth signal transduction pathway by a GST-fused constitutively active mutant of a kinase protein. These PEI-glutathione conjugates seem to be convenient molecular tools for protein transduction of widely used GST-fused proteins.

DOI： 10.1093/jb/mvn087

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Derivation of hepato-pancreatic intermediate progenitor cells from a clonal mesenchymal stem cell line of rat bone marrow origin

Takuro Masaka, Masahiro Miyazaki, Gang Du, Marhaen Hardjo, Masakiyo Sakaguchi, Mikiro Takaishi, Ken Kataoka, Kazuhide Yamamoto, Nam-Ho Huh

INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 22 ( 4 ) 447 - 452 2008.10

Language：English Publisher：PROFESSOR D A SPANDIDOS

We have recently established a clonal mesenchymal stem cell line (rBM25/S3) from adult rat bone marrow. The cells have practically unlimited proliferation capacity (over 300 PDL), maintaining multipotency for differentiation. In the present study, we examined the potential for rBM25/S3 cells to differentiate into insulin-secreting cells. When cultured in the presence of HGF and FGF-4 on Matrigel, rBM25/S3 cells expressed genes specific to pancreatic B-cells as well as those specific to hepatocytes. They still maintained proliferation capacity with a doubling time of similar to 30 h. These hepato-pancreatic intermediate progenitor cells, but not the original undifferentiated rBM25/S3 cells, were induced by the overexpression of PDX-1 to produce significant amounts of insulin in a manner responding to glucose concentration in medium. The present culture system indicates a direction for further studies aimed at the realization of cell transplantation therapy for type I diabetes mellitus.

DOI： 10.3892/ijmm_00000041

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An N-terminal 78 amino acid truncation of REIC/Dkk-3 effectively induces apoptosis

Fernando Abarzua, Yuji Kashiwakura, Munenori Takaoka, Masami Watanabe, Kazuhiko Ochiai, Masakiyo Sakaguchi, Takao Iwawaki, Ryuta Tanimoto, Yasutomo Nasu, Nam-ho Huh, Hiromi Kumon

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 375 ( 4 ) 614 - 618 2008.10

Language：English Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Overexpression of REIC/Dkk-3 (a tumor suppressor gene) induces cancer cell apoptosis through endoplasmic reticulum (ER) stress. Therefore, the identification of the portion of REIC/Dkk-3 that causes ER stress may be essential for the development of cancer treatment based on REIC/Dkk-3. Here, we made several truncated forms of REIC/Dkk-3 and investigated their therapeutic potentials against prostate cancer. Among three truncated forms, a variant comprising the N-terminal 78 amino acid region of REIC/Dkk-3 ((1-78) REIC/Dkk-3) most strongly induced ER stress and apoptosis in human prostate cancer cells (PC3). For in vivo gene expression, we coupled a biodegradable polymer with naked DNA, which attained robust trans-gene expression in PC3-derived subcutaneous tumor. In therapeutic experiments, we demonstrated that multiple direct injections of polymer-conjugated (1-78)REIC/Dkk-3 plasmid provoke ER stress and significantly reduced the subcutaneous tumor volume compared with the control group. We suggest this non-viral strategy may be an effective alternative to viral gene therapy. (C) 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2008.08.079

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Down-regulation of Inhibition of Differentiation-1 via Activation of Activating Transcription Factor 3 and Smad Regulates REIC/Dickkopf-3-Induced Apoptosis

Yuji Kashiwakura, Kazuhiko Ochiai, Masami Watanabe, Fernando Abarzua, Masakiyo Sakaguchi, Munenori Takaoka, Ryuta Tanimoto, Yasutomo Nasu, Nam-ho Hub, Hiromi Kumon

CANCER RESEARCH 68 ( 20 ) 8333 - 8341 2008.10

Language：English Publisher：AMER ASSOC CANCER RESEARCH

REIC/Dickkopf-3 (Dkk-3), a tumor suppressor gene, has been investigated in gene therapy studies. Our previous study suggested that REIC/Dkk-3-induced apoptosis mainly resulted from phosphorylation of c-Jun-NH2 kinase (JNK) in prostate cancer cells. However, the precise mechanisms, especially the molecular mechanisms regulating JNK phosphorylation, remain unclear. In this study, we investigated the mechanisms participating in JNK phosphorylation in the context of a refractory cancer disease, malignant mesothelioma (MM). Adenovirus-mediated overexpression of REIC/Dkk-3 induced apoptosis mainly through JNK activation in immortalized MM cells (211H cells). Interestingly, transcriptional down-regulation of inhibition of differentiation-1 (Id-1) was detected in REIC/Dkk-3-overexpressed 211H cells. Moreover, restoration of Id-1 expression antagonized REIC/Dkk-3-induced JNK phosphorylation and apoptosis. Mutagenesis experiments with the 2.1-kb human Id-1 promoter revealed that activating transcription factor 3 (ATF3) and Smad interaction, with their respective binding motifs, was essential for REIC/Dkk-3-mediated suppression of Id-1 promoter activity. ATF3 activation was probably induced by endoplasmic reticulum stress. Finally, we showed strong antitumor effects from REIC/Dkk-3 gene transfer into the pleural cavity in an orthotopic MM mouse model. Relative to control tumor tissue, REIC/Dkk-3-treated tumor tissue showed down-regulated expression of Id-1 mRNA, enhanced expression of phosphorylated JNK, and an increased number of apoptotic cells. In summary, we first showed that both ATF3 and Smad were crucially and synergistically involved in down-regulation of Id-1, which regulated JNK phosphorylation in REIC/Dkk-3-induced apoptosis. Thus, gene therapy with REIC/Dkk-3 may be a promising therapeutic tool for MM. [Cancer Res 2008;68(20):8333-41]

DOI： 10.1158/0008-5472.CAN-08-0080

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REIC/Dkk-3遺伝子治療の正常細胞を介する抗腫瘍効果(Transduction of gene therapeutic REIC/Dkk-3 into normal cells provides another arm for tumor suppression in vivo)

片岡健, 阪口政清, Fernando Abarzua, 谷本竜太, 渡部昌実, 村田等, 那須保友, 公文裕巳, 許南浩

日本癌学会総会記事 67回 93 - 93 2008.9

REIC/Dkk-3遺伝子によるアポトーシス耐性メカニズムとその克服(BiP is a determining protein for sensitivity to apoptosis induced by a gene-therapeutic adenovirus carrying REIC/Dkk-3)

谷本竜太, 阪口政清, アバルズア・フェルナンド, 片岡健, 那須保友, 公文裕巳, 許南浩

日本癌学会総会記事 67回 238 - 238 2008.9

REIC/Dkk-3の強制発現はERストレスを介してIL-7を誘導する(Over-expression of REIC/Dkk-3 induces IL-7 in normal human fibroblasts via ER stress)

阪口政清, 片岡健, アバルスア・フェルナンド, 谷本竜太, 渡辺昌実, 村田等, 那須保友, 公文裕己, 許南浩

日本癌学会総会記事 67回 238 - 238 2008.9

BRPK/PINK1はAktのリン酸化によってがん細胞のアポトーシスを抑制する(BRPK/PINK1 blocks apoptotic cell death of cancer cells by phosphotylation of Akt)

村田等, 阪口政清, 片岡健, 許南浩

日本癌学会総会記事 67回 64 - 64 2008.9

S100A8/A9, a key mediator for positive feedback growth stimulation of normal human keratinocytes

Takamasa Nukui, Ritsuko Ehama, Masakiyo Sakaguchi, Hiroyuki Sonegawa, Chika Katagiri, Toshihiko Hibino, Nam-Ho Huh

JOURNAL OF CELLULAR BIOCHEMISTRY 104 ( 2 ) 453 - 464 2008.5

Language：English Publisher：WILEY-LISS

S100A8 and S100A9 are known to be up-regulated in hyperproliferative and psoriatic epidermis, but their function in epidermal keratinocytes remains largely unknown. Here we show that (1) S100A8 and S100A9 are secreted by cultured normal human keratinocytes (NHK) in a cytokine-dependent manner, (2) when applied to NHK, recombinant S100A8/A9 (a 1:1 mixture of S100A8 and S100A9) induced expression of a number of cytokine genes such as IL-8/CXCL8, CXCL1, CXCL2, CXCL3, CCL20, IL-6, and TNF alpha that are known to be up-regulated in psoriatic epidermis, (3)the S100A8/ A9-induced cytokines in turn enhanced production and secretion of S100A8 and S100A9 by NHK, and (4) S100A8 and S100A8/A9 stimulated the growth of NHK at a concentration as low as 1 ng/ml. These results indicate the presence of a positive feedback loop for growth stimulation involving S100A8/A9 and cytokines in human epidermal keratinocytes, implicating the relevance of the positive feedback loop to the etiology of hyperproliferative skin diseases, including psoriasis.

DOI： 10.1002/jcb.21639

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S100A11 functions as a dual mediator for growth regulation in normal human keratinocytes

M. Sakaguchi, H. Murata, N. Huh

JOURNAL OF INVESTIGATIVE DERMATOLOGY 128 S138 - S138 2008.4

Serum calcium-binding S100A8/A9 proteins in patients with psoriatic arthritis are derived from not only the skin lesions but also circulating monocytes

S. Aochi, K. Tsuji, M. Sakaguchi, N. Huh, T. Tsuda, K. Yamanishi, M. Komine, K. Iwatsuki

JOURNAL OF INVESTIGATIVE DERMATOLOGY 128 S17 - S17 2008.4

S100A11, an dual mediator for growth regulation of human keratinocytes

Masakiyo Sakaguchi, Hiroyuki Sonegawa, Hitoshi Murata, Midori Kitazoe, Jun-ichiro Futami, Ken Kataoka, Hidenori Yamada, Nam-ho Huh

MOLECULAR BIOLOGY OF THE CELL 19 ( 1 ) 78 - 85 2008.1

Language：English Publisher：AMER SOC CELL BIOLOGY

We previously revealed a novel signal pathway involving S100A11 for inhibition of the growth of normal human keratinocytes (NHK) caused by high Ca++ or transforming growth factor beta. Exposure to either agent resulted in transfer of S100A11 to nuclei, where it induced p21(WAF1). In contrast, S100A11 has been shown to be overexpressed in many human cancers. To address this apparent discrepancy, we analyzed possible new functions of S100A11, and we provide herein evidence that 1) S100A11 is actively secreted by NHK; 2) extracellular S100A11 acts on NHK to enhance the production of epidermal growth factor family proteins, resulting in growth stimulation; 3) receptor for advanced glycation end products, nuclear factor-kappa B, Akt, and cAMP response element-binding protein are involved in the S100A11-triggered signal transduction; and 4) production and secretion of S100A11 are markedly enhanced in human squamous cancer cells. These findings indicate that S100A11 plays a dual role in growth regulation of epithelial cells.

DOI： 10.1091/mbc.E07-07-0682

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Truncation of annexin A1 is a regulatory lever for linking epidermal growth factor signaling with cytosolic phospholipase A2 in normal and malignant squamous epithelial cells

Masakiyo Sakaguchi, Hitoshi Murata, Hiroyuki Sonegawa, Yoshihiko Sakaguchi, Jun-ichiro Futami, Midori Kitazoe, Hidenori Yamada, Nam-ho Huh

JOURNAL OF BIOLOGICAL CHEMISTRY 282 ( 49 ) 35679 - 35686 2007.12

Language：English Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Regulation of cell growth and apoptosis is one of the pleiotropic functions of annexin A1 (ANXA1). Although previous reports on the overexpression of ANXA1 in many human cancers and on growth suppression and/or induction of apoptosis by ANXA1 may indicate the tumor-suppressive nature of ANXA1, molecular mechanisms of the function of ANXA1 remain largely unknown. Here we provide evidence that ANXA1 mechanistically links the epidermal growth factor-triggered growth signal pathway with cytosolic phospholipase A(2) (cPLA(2)), an initiator enzyme of the arachidonic acid cascade, through interaction with S100A11 in normal human keratinocytes (NHK). Ca2+ -dependent binding of S100A11 to ANXA1 facilitated the binding of the latter to cPLA2, resulting in inhibition of cPLA2 activity, which is essential for the growth of NHK. On exposure of NHK to epidermal growth factor, ANXA1 was cleaved solely at Trp(12), and this cleavage was executed by cathepsin D. In squamous cancer cells, this pathway was shown to be constitutively activated. The newly found mechanistic intersection may be a promising target for establishing new measures against human cancer and other cell growth disorders.

DOI： 10.1074/jbc.M707538200

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Isolation of a bone marrow-derived stem cell line with high proliferation potential and its application for preventing acute fatal liver failure

Masahiro Miyazaki, Marhaen Hardjo, Takuro Masaka, Koji Tomiyama, Naila Mahmut, Reinhold J. Medina, Aya Niida, Hiroyuki Sonegawa, Gang Du, Rong Yong, Mikiro Takaishi, Masakiyo Sakaguchi, Nam-Ho Huh

STEM CELLS 25 ( 11 ) 2855 - 2863 2007.11

Language：English Publisher：ALPHAMED PRESS

Transplantation of hepatocytes or hepatocyte-like cells of extrahepatic origin is a promising strategy for treatment of acute and chronic liver failure. We examined possible utility of hepatocyte-like cells induced from bone marrow cells for such a purpose. Clonal cell lines were established from the bone marrow of two different rat strains. One of these cell lines, rBM25/S3 cells, grew rapidly (doubling time, similar to 24 hours) without any appreciable changes in cell properties for at least 300 population doubling levels over a period of 300 days, keeping normal diploid karyotype. The cells expressed CD29, CD44, CD49b, CD90, vimentin, and fibronectin but not CD45, indicating that they are of mesenchymal cell origin. When plated on Matrigel with hepatocyte growth factor and fibroblast growth factor-4, the cells efficiently differentiated into hepatocyte-like cells that expressed albumin, cytochrome P450 (CYP) 1A1, CYP1A2, glucose 6-phosphatase, tryptophane-2,3-dioxygenase, tyrosine aminotransferase, hepatocyte nuclear factor (HNF)1 alpha, and HNF4 alpha. Intrasplenic transplantation of the differentiated cells prevented fatal liver failure in 90%-hepatectomized rats. In conclusion, a clonal stem cell line derived from adult rat bone marrow could differentiate into hepatocyte-like cells, and transplantation of the differentiated cells could prevent fatal liver failure in 90%-hepatectomized rats. The present results indicate a promising strategy for treating human fatal liver diseases.

DOI： 10.1634/stemcells.2007-0078

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ヒト膀胱癌細胞におけるREIC/Dkk-3誘導性アポトーシスに対する抵抗性の機構解析(Mechanistic Analysis of Resistance to REIC/Dkk-3-induced Apoptosis in Human Bladder Cancer Cell Lines)

小林知子, 阪口政清, 谷本竜太, 枝村康平, アバラズア・フェルナンド, 片岡健, 賀来春紀, 雑賀隆史, 宮崎正博, 那須保友, 公文裕巳, 許南浩

西日本泌尿器科 69 ( 増刊 ) 125 - 125 2007.10

Adenovirus-mediated REIC/Dkk-3 gene transfer inhibits tumor growth and metastasis in an orthotopic prostate cancer model

K. Edamura, Y. Nasu, M. Takaishi, T. Kobayashi, F. Abarzua, M. Sakaguchi, Y. Kashiwakura, S. Ebara, T. Saika, M. Watanabe, N-H Huh, H. Kumon

CANCER GENE THERAPY 14 ( 9 ) 765 - 772 2007.9

Language：English Publisher：NATURE PUBLISHING GROUP

We had previously reported that REIC/Dkk-3, a member of the Dickkopf ( Dkk) gene family, works as a tumor suppressor. In this study, we evaluated the therapeutic effects of an intratumoral injection with adenoviral vector encoding REIC/Dkk-3 gene ( Ad-REIC) using an orthotopic mouse prostate cancer model of RM-9 cells. We also investigated the in vivo anti-metastatic effect and in vitro anti-invasion effect of Ad-REIC gene delivery. We demonstrated that the Ad-REIC treatment inhibited prostate cancer growth and lymph node metastasis, and prolonged mice survival in the model. These therapeutic responses were consistent with the intratumoral apoptosis induction and in vitro suppression of cell invasion/migration with reduced matrix metalloprotease-2 activity. We thus concluded that in situ Ad-REIC/Dkk-3 gene transfer may be a promising therapeutic intervention modality for the treatment of prostate cancer.

DOI： 10.1038/sj.cgt.7701071

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ヒト膀胱癌細胞株におけるREIC/Dkk-3誘導性アポトーシスに対する抵抗性の機構的解析(Mechanistic Analysis of Resistance to REIC/Dkk-3-induced Apoptosis in Human Bladder Cancer Cell Lines)

小林知子, 阪口政清, 谷本竜太, アバラズア・フェルナンド, 高石樹朗, 片岡健, 賀来春紀, 雑賀隆史, 那須保友, 宮崎正博, 公文裕巳, 許南浩

日本癌学会総会記事 66回 476 - 476 2007.8

Heat shock proteins play a crucial role in tumor-specific apoptosis by REIC/Dkk-3

Fernando Abarzua, Masakiyo Sakaguchi, Ryuta Tanimoto, Hiroyuki Sonegawa, Dai-Wei L, Kohei Edamura, Tomoko Kobayashi, Masami Watanabe, Yuji Kashiwakura, Haruki Kaku, Takashi Saika, Keiichiro Nakamura, Yasutomo Nasu, Hiromi Kumon, Nam-Ho Huh

INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 20 ( 1 ) 37 - 43 2007.7

Language：English Publisher：PROFESSOR D A SPANDIDOS

We recently showed that overexpression of REIC/Dickkopf-3 (Dkk-3), a tumor suppressor gene, induced apoptosis in a tumor cell-specific manner. The aim of the present study was to determine the mechanisms underlying the selective induction of apoptosis. At first, we found a mouse renal carcinoma cell line, RENCA, to be extremely sensitive to an adenovirus carrying REIC/Dkk-3 (Ad-REIC), and we showed that activation of c-Jun N-terminal kinase (JNK) was a critical step in cell death, i.e. a process similar to that in human prostate and testicular cancer observed in our previous studies. Among the proteins interfering with the activation of JNK, heat shock protein (Hsp)70/72 was reduced in expression in RENCA cells compared with that in NIH3T3 cells. An Hsp70/72 inducer protected RENCA cells from Ad-REIC-induced apoptosis, while an Hsp70/72 inhibitor sensitized NIH3T3 cells for apoptosis induction. These results indicate that functionally active Hsp70/72 is a key factor in tumor cell-specific induction of apoptotic cell death and that analyses of the expression levels of Hsp70/72 may be essential in determining the significance of Ad-REIC-based gene therapy against human cancer.

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