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| Career Summary |
1990: B.Sc., Faculty of Pharmaceutical Sciences, The University of Tokyo
1995: Ph.D. (Doctor of Pharmaceutical Sciences), The University of Tokyo
1993-1995: Predoctoral Fellow in Cancer Research, Japan Society for the Promotion of Science
1995-2004: Research Associate, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research
2000-2001: Postdoctoral Fellow, New York University School of Medicine
2004: Associate Member, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research
2005-Present: Member and Chief (Principal Investigator), Cancer Chemotherapy Center, Japanese Foundation for Cancer Research
2008-Present: Visiting Professor, Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University (concurrent)
2009-Present: Visiting Professor, Institute of Health Biosciences, The University of Tokushima Graduate School (concurrent)
2010-Present: Visiting Associate Professor, Graduate School of Frontier Sciences, The University of Tokyo (concurrent)
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| Educational Activities |
Faculty of Pharmaceutical Sciences, The University of Tokyo
Graduate School of Pharmaceutical Sciences, Keio University
Graduate School of Biomedical Sciences, Hiroshima University
The Japanese Red Cross College of Nursing
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| Research Activities |
1. Telomere dynamics and cancer
To proliferate, cells need to replicate their DNA. However, classical replication machinery cannot completely replicate the very ends of chromosomes (telomeres). Thus telomeres, specialized structures that protect eukaryotic chromosome termini, gradually shorten after each cell cycle. When telomeres reach the limit of shortening, the cells cannot divide any further. This phenomenon, called replicative senescence (gagingh of a cell), is one of the systems that prevent carcinogenesis. In most cancer cells, the telomere-synthesizing enzyme, telomerase, stably maintains telomeres. Accordingly, cancer cells have the ability to divide infinitely. We have developed a series of telomerase inhibitors (e.g., MST-312, 295, 199) that block the unlimited growth of cancer cells. We also found that each cancer cell line exhibits a differential telomere status, in terms of its DNA length and composition of the binding proteins. Now we would like to understand the total landscape of the molecular network that regulates telomere dynamics, and its relation to cancer cell biology and the efficacies of newly designed telomere-recognizing compounds.
2. Cell regulation by poly(ADP-ribosyl)ation
Poly(ADP-ribosyl)ation (PARsylation), one of the most drastic post-translational modifications of proteins, is catalyzed by poly(ADP-ribose) polymerases (PARP). PARsylation regulates various biological events, including genomic stability, gene transcription, and so forth. We still have many questions about this process, such as the molecular basis for functional specificity elicited from PAR chains. Recent reports including ours show that PARP inhibitors could be utilized as novel anticancer drugs. We focus on tankyrases, the PARP members that enhance telomere elongation by telomerase in human cancer cells. We are working on the multi-functionality of tankyrases and a novel strategy for PARP-based cancer therapeutics.
3. Lipid metabolism in cancer
In many cancers, de novo fatty acid synthesis is enhanced irrespective of the levels of exogenous lipids. Since some lipogenic enzymes, such as fatty acid synthase (FASN), are involved in carcinogenesis and its malignant progression, they could be postulated as molecular targets for cancer therapy. We found that acyl-CoA synthetase (ACS) is essential for the growth of some cancers and their survival in unfavorable tumor microenvironments. Furthermore, ACS inhibition boosted the efficacy of classical anticancer drugs. We are investigating the underlying mechanisms for these phenomena and functional involvement of other lipogenic enzymes, such as ATP citrate lyase (ACLY).
4. Conquest of castration-resistant prostate cancers
Prostate cancer cell growth depends on androgens. Endocrine therapy blocks this hormonal signaling and displays anticancer efficacy in clinical settings. However, frequent relapse of refractory cancers remains to be overcome. In castration-resistant prostate cancers (CRPC), the androgen receptor promotes the cell growth even without androgens. Furthermore, they often fail to execute an apoptotic (innate cell suicide) program upon treatment with conventional anticancer drugs. Employing functional genetics and chemical biology, we are pursuing rational therapeutic targets for CRPC.
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Literature
1. Ohishi, T., Hirota, T., Tsuruo, T. and Seimiya, H. TRF1 mediates mitotic abnormalities induced by Aurora-A overexpression.
Cancer Res, 70: 2041-2052, 2010.
2. Migita, T., Narita, T., Asaka, R., Miyagi, E., Nagano, H., Nomura, K., Matsuura, M., Satoh, Y., Okumura, S., Nakagawa, K., Seimiya, H. and Ishikawa, Y. Role of insulin-like growth factor binding protein 2 in lung adenocarcinoma: IGF-independent antiapoptotic effect via caspase-3.
Am J Pathol, 176: 1756-1766, 2010.
3. McCabe, N., Cerone, M. A., Ohishi, T., Seimiya, H., Lord, C. J. and Ashworth, A. Targeting Tankyrase 1 as a therapeutic strategy for BRCA-associated cancer.
Oncogene, 28: 1465-1470, 2009.
4. Mashima, T., Sato, S., Sugimoto, Y., Tsuruo, T. and Seimiya, H. Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions.
Oncogene, 28: 9-19, 2009.
5. Migita, T., Narita, T., Nomura, K., Miyagi, E., Inazuka, F., Matsuura, M., Ushijima, M., Mashima, T., Seimiya, H., Satoh, Y., Okumura, S., Nakagawa, K. and Ishikawa, Y. ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer.
Cancer Res, 68: 8547-8554, 2008.
6. Tahara, H., Shin-Ya, K., Seimiya, H., Yamada, H., Tsuruo, T. and Ide, T. G-Quadruplex stabilization by telomestatin induces TRF2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3' telomeric overhang in cancer cells.
Oncogene, 25: 1955-1966, 2006.
7. Seimiya, H., Muramatsu, Y., Ohishi, T. and Tsuruo, T. Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics.
Cancer Cell, 7: 25-37, 2005.
8. Seimiya, H., Muramatsu, Y., Smith, S. and Tsuruo, T. Functional subdomain in the ankyrin domain of tankyrase 1 required for poly(ADP-ribosyl)ation of TRF1 and telomere elongation.
Mol Cell Biol, 24: 1944-1955, 2004.
9. Motiwala, T., Kutay, H., Ghoshal, K., Bai, S., Seimiya, H., Tsuruo, T., Suster, S., Morrison, C. and Jacob, S. T. Protein tyrosine phosphatase receptor-type O (PTPRO) exhibits characteristics of a candidate tumor suppressor in human lung cancer.
Proc Natl Acad Sci USA, 101: 13844-13849, 2004.
10. Seimiya, H. and Smith, S. The telomeric poly(ADP-ribose) polymerase, tankyrase 1, contains multiple binding sites for telomeric repeat binding factor 1 (TRF1) and a novel acceptor, 182-kDa tankyrase-binding protein (TAB182).
J Biol Chem, 277: 14116-14126, 2002.
11. Seimiya, H., Oh-hara, T., Suzuki, T., Naasani, I., Shimazaki, T., Tsuchiya, K. and Tsuruo, T. Telomere shortening and growth inhibition of human cancer cells by novel synthetic telomerase inhibitors MST-312, MST-295, and MST-199.
Mol Cancer Ther, 1: 657-665, 2002.
12. Seimiya, H., Sawada, H., Muramatsu, Y., Shimizu, M., Ohko, K., Yamane, K. and Tsuruo, T. Involvement of 14-3-3 proteins in nuclear localization of telomerase.
EMBO J, 19: 2652-2661, 2000.
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| Other Activities |
Japanese Cancer Association (Councilor)
The Japanese Association for Molecular Target Therapy of Cancer (Councilor)
The JFCR International Symposium on Cancer Chemotherapy (Committee Member)
Anti-Tumor Drug Development Forum (Councilor)
Molecular Biology Society of Japan
The Pharmaceutical Society of Japan
Japanese Society of Medical Oncology
American Association for Cancer Research
Japanese Association for RNA Interference
Associate Editor, Cancer Science
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| Future Plan |
Our goals are to pinpoint the Achilles' heels of cancers at the molecular level and to develop anticancer therapeutics directed against such molecular targets. We especially focus on (i) telomeres, which are associated with cellular replicative capacity, (ii) poly(ADP-ribose) polymerases, which are involved in genomic stability, (iii) lipid metabolism that is enhanced in cancer cells, and (iv) signal transduction by the androgen receptor, which contributes to the growth and relapse of prostate cancers. We would like to elucidate the molecular bases of system failures in those events and cure cancers by correcting or blocking them.
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| Messages to Students |
Gradually aging cells seen with a microscope will remind you that you only live once. Asking yourself how you can enrich your limited life will make your thought and action proactive. Proactive thought and action are not only essential for conducting research but will also, I believe, motivate your neighbors. Good luck with your life and research.
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