Research Focus
The studies in our laboratory focus on the molecular mechanism of tumor metastasis. The development of metastasis is a major obstacle to the successful treatment of a patient with any cancer. Much of the lethality of malignant neoplasm is attributable directly to its ability to develop secondary growths in organs distant from the primary tumor mass, while few patients die from their primary neoplasm. Although the clinical importance of the tumor metastasis is well recognized, advances in understanding the molecular mechanism involved in metastasis formation have lagged behind other developments in the cancer field. Like many other disease processes, metastasis involves multi-steps with high complexity and is controlled by a variety of positive and negative factors. Our lab is particularly interested in the roles of tumor metastases suppressor genes, KAI-1 and Drg-1, that are capable of suppressing the process of metastasis.
The KAI-1 gene is located in the p11.2 region of human chromosome 11, and it is down-regulated during the tumor progression of most epithelial type tumors including prostate, lung, breast, bladder and pancreatic cancers. Our recent results indicate that the KAI-1 gene is directly controlled by the p53 gene, and therefore, loss of p53 leads to the down-regulation of KAI1. We have also shown that the expression of the KAI-1 gene can be restored by p53-inducing drugs including etoposide, suggesting a potential utility of such drugs for the treatment of metastatic disease. How KAI-1 suppresses metastasis is of paramount interest. Our approach to this question using the yeast two hybrid system revealed that KAI-1 interacts with a protein on the surface of endothelial cells and that this interaction leads to tumor cell death. We are currently characterizing the nature of this interaction and exploring the possibility to develop a drug to activate the KAI-1 pathway for therapeutic application.
Drg-1 was originally identified as a differentiation-related gene for a colon cell. While characterizing this gene, we found that Drg-1 significantly suppresses tumor metastases without affecting primary tumor formation in our animal model of prostate cancer. This observation was further supported by our analysis of clinical specimens of breast and prostate cancers. Drg-1 is in most cases down-regulated in these types of tumors and this down-regulation is correlated with poor survival of the patients. Therefore, evidence from both clinical data and the results of in vitro as well as animal experiments strongly support the notion that Drg-1 is a metastasis suppressor gene and that the down-regulation of the gene results in acceleration of tumor metastasis. Our results also indicate that the expression of the Drg-1 gene is regulated by promoter methylation as well as by the tumor suppressor gene, PTEN. Therefore, the expression of the Drg-1 gene is controlled by both genetic and epigenetic factors. To understand the molecular mechanism of the metastasis suppression by Drg-1, we are currently conducting microarray analysis to identify the down-stream targets. We are also performing yeast two hybrid screening as well as proteomics to identify a molecule interacting with the Drg-1 protein. Our long-term goal is to construct a molecular map of metastasis suppressors and to elucidate the mechanisms of tumor metastasis, which can eventually lead to better diagnostic markers and therapeutic remedies for this devastating disease.
Another focus of our research is the role of fatty acid synthase (FAS) in tumor progression. FAS is specifically over-expressed in many epithelial cell tumors, and our immunohistochemical analysis of both prostate and breast cancer specimens revealed that the expression of FAS is significantly correlated with the progression of these types of cancers and poor survival of patients. Therefore, FAS is considered to be an ideal therapeutic target for drug development. Our in vitro data indicate that the expression of the FAS gene is partly controlled by the PI3/AKT pathway, and blocking the pathway suppresses the expression of the FAS gene. Furthermore, we have recently found that siRNA specific to the FAS gene induces apoptosis due to the suppression of carnitine palmitoyltransferase I followed by accumulation of ceramide and concomitant activation of pro-apoptotic genes, BNIP3, TRAIL and DAPK2. We are currently screening a small molecule which is capable of blocking the dimer formation of FAS protein so that such a molecule can be used for the treatment of cancer patients.
Representative Publications
Megumi Iiizumi, Sucharita Bandyopadhyay, Sudha K Pai, Misako Watabe, Shigeru Hirota, Sadahiro Hosobe, Taisei Tsukada, Kunio Miura, Ken Saito, Eiji Furuta, Wen Liu, and Kounosuke Watabe (2008). RhoC promotes metastasis via activation of Pyk2 pathway in prostate cancer. Cancer Res. In press
Megumi Iiizumi, Wen Liu, and Kounosuke Watabe (2008). Drug development against metastasis-related gene and their pathways: A rationale for cancer therapy. BBA Cancer Review. In press
Aya Kobayashi, Kounosuke Watabe (2008) Critical role of ADAM15 in tumor progression: targeting multiple factors for metastasis promotion. Future Oncology. 4. 351
Furuta, E., Pai, SK., Zhan, R., Bandyopadhyay, S., Watabe, M., Iiizumi, M., Liu, W., Mo, Y-Y., Hirota, S., Hosobe, S.,Tsukada,T., Miura,K., Kamada, S., Saito, K. and Watabe, K. (2008) Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and SREBP. Cancer Res. 68, 1003
Iiizumi, K., Mohinta, S., Bandyopadhyay, S. and Watabe, K. (2007) Tumor - endothelial cell interactions: Therapeutic potential. Microvascular Research. 74:114-20
Iiizumi, M., Bandyopadhyay, S. and Watabe, K. (2007) Interaction of DARC and KAI1: a critical step in metastasis suppression. Cancer Res. 15, 1411-14
Bandyopadhyay, S and Watabe, K. (2007) The Tumor Metastasis Suppressor Gene Drg-1 in Cancer Progression and metastasis in “New Developments in Metastasis Suppressor Research” Ed. Paul Jackson. Nova Publishers. pp87-102
Liu, W., Bagaitkar, K. and Watabe, K. (2007) Roles of AKT signal in breast cancer. Frontier in Bioscience. 12:4011-9.
Mohinta, S., Wu, H., Chaurasia, P. and Watabe, K. (2007) Wnt Pathway and Breast Cancer. Frontier in Bioscience. 12: 4020-33
Bandyopadhyay, S., Zhan,R., Chaudhuri, A., Watabe, M., Pai, SK., Hirota, S., Hosobe, S., Tsukada,T., Miura,K., Takano,Y., Saita,K., Pauza,ME., Hayashi,S., Wang,Y., Mohinta,S., Mashimo,T., Iiizumi. M., Furuta,E and Watabe, K. (2006) Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression. Nature Medicine, 12: 933-9388
Bandyopadhyay, S., Wang, Y., Zhan, R., Pai, SK., Watabe, M., Iiizumi, M., Furuta, E., Mohinta, S., Liu, W., Hirota, H., Hosobe, S., Tsukada, T., Miura, K., Takano, Y., Saito, K., Commes, T., Piquemal, D., Hai, T. and Watabe, K. (2006) The tumor metastasis suppressor gene Drg-1 down regulates the expression of ATF3 in prostate cancer. Cancer Res. 66:11983-90.
Bandyopadhyay, S., Zhan, R., Wang, Y., Pai, SK., Hirota, S., Hosobe, S., Takano, Y., Saito, K., Furuta, E., Iiizumi, M., Mohinta, S., Watabe, M., Chalfant, C., and Watabe, K.(2006) Mechanism of apoptosis induced by the inhibition of Fatty Acid Synthase in breast cancer cells. Cancer Res. 66, 5934-5940
Furuta, E., Bandyopadhyay, S., Iiizumi,M., Mohinta,S., Zhan,R and Watabe, K. (2006) The role of metastasis suppressors in cancers of breast and prostate (Review). Frontier in Bioscience. 11, 2845-2860
Malafa, M., Fokum, F., Andoh, J., Neitzel, L., Bandyopadhyay, S., Zhan, R., Iiizumi, M., Furuta E. and Watabe. K (2006) Vitamine succinate suppesses prostate tumor growth by inducing apoptosis. Int. J. Cancer. 2006 15;118(10):2441-7
Furuta E., Yamamoto K., Tatebe D., Watabe K., Kitayama T. and Utsumi R.(2005) Targeting protein homodimerization: A novel drug discovery system. FEBS 579, 2065-70
Bandyopadhyay, S., Pai, SK., Gross, SC., Hirota, S., Hosobe, S., Tsukada, T., Miura, K., Saito, K., Watabe, M., Wang Y., Huggenvik, J. Pauza, ME, Iiizumi, M. and Watabe K.(2005) FAS expression inversely correlates with PTEN level in prostate cancer and an Akt inhibitor synergizes with FAS siRNA to induce apoptosis. Oncogene, 24, 5389
Bandyopadhyay, S., Pai, S.K., Hirota, S., Hosobe, S., Tsukada, T., Miura, K., Takano Y., Saito, K., Piquemal, D., Commes, T., Watabe, M., Gross, S.C., Wang, Y., Huggenvik, J.and Watabe K (2004) PTEN up-regulates the tumor metastasis suppressor gene Drg-1 in prostate and breast cancer. Cancer Res. 64(21):7655-60.
Bandyopadhyay, S., Pai, S.K., Hirota, S., Hosobe, S., Takano Y., Saito, K., Piquemal, D., Commes, T., Watabe, M., Gross, S.C., Wang, Y., Ran S., and Watabe K. (2004) Role of the putative tumor metastasis suppressor gene Drg-1 in breast cancer progression. Oncogene, 23, 5675-81
Struble, RG, Rosario, E., Kircher, M., Ludwig, S., McAdamis, P., Watabe, K., McAsery, M., Cady, C. and Nathan, BP. (2003) Regionally specific modulation of brain apolipoprotein E in the mouse during the estrous cycle and by exogenous 17beta estradiol. Exp Neurol. 183(2):638-44.
Bandyopadhyay S, and Watabe K. (2003) Roles of tumor metastasis suppressor genes in cancer progression. Recent research developments in Biochemistry. 4:697-720. Research Signpost
Bandyopadhyay, S. Sudha, K. Pai, Steven C. Gross., Hirota, H., Hosobe, S., Miura, H., Saito, K., Therese Commes., Watabe, M. and Watabe K. (2003) The Drg-1 gene suppresses tumor metastasis in prostate cancer. Cancer Res. 63. 1731-1736
Gross. S. Goodarzi, G., Watabe, M. Bandyopadhyay, S., Pai, SK., and Watabe, K. (2002) Anti-enoplastic activity of Solidago virgaurea on prostatic tumor cells in a SCID mouse model. Nutrition and Cancer, 43, 76-81
Goodarzi, G., Mashimo, T., Watabe, M., Cuthbert, AP., Newbold, RF., Pai, SK., Horota, S., Hosobe, S., Miura, K., Bandyopadyay, S., Gross, S. and Watabe, K.(2001) Identification of tumor metastasis suppressor region on the short arm of human chromosome 20. Genes Chromosome and Cancer. 32,33-42
Mashimo, T., Bandyopadhyay, S., Goodarzi, G., Watabe, M., Pai, S., Gross, S. and Watabe, K. (2000) Activation of the tumor metastasis suppressor gene, KAI1, by etoposide is mediated by p53 and c-Jun genes. Biochem. Biophys. Res. Com. 274. 370-376
Mashimo T., Goodarzi, G., Watabe, M., Cuthbert, A.P., Newbold, R.F., Pai, S.K., Hirota, S., Hosobe, S., Miura, K., Bandyopadhyay, S., Gross, S.C., and Watabe, K. (2000). Localization of a novel tumor metastasis suppressor region on human chromosome 2 short arm. Genes Chromosome and Cancer. 28, 285-293
Luu, H.H., Zagaja, G.P., Dabauskas, Z., Smith, R.C., Watabe, K., Ichikawa, Y., Ichikawa, T., and Rinker- Schaeffer, C.W. (1998). Identification of a novel prostate cancer metastasis-suppressor region on human chromosome 12. Cancer Res. 51:3561-3565.
Mashimo, T., Watabe, M., Cuthbert, A.P., Newbold, R.F., Rinker-Schaeffer, C.W., Helfer, E. and Watabe, K. (1998). Human chromosome 16 suppresses metasasis of rat prostate tumor cell. Cancer. Res.. 58:4572-4576.
Yoshida, B., Chekmareva, M., Wharam. J.F., Kadkhodaian, M., Stadler, W., Boyer, A., Watabe, K., Nelson, J.B., and Rinker-Schaeffer, C.W. (1998). Prostate cancer metastasis suppressor genes: A current perspective. In vitro 12:49-58.
Mashimo, T., Watabe, M., Hirota, S., Hosobe, S., Tagymyer, P., Rinker-Schaefer, C. and Watabe, K. (1998). The expression of the KAI1 gene, a tumor metastasis suppressor, is directly activated by p53. Proc. Natl Acad. Sci. USA 95:11307-11311.
Members of Watabe lab
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