COM4S_M.TTF

Research Focus

Prostate cancer is the most common cancer in males and is the second leading cause of cancer-related deaths in males in the United States . This laboratory studies the relationship between androgenic (male) steroids and the development and progression of prostate cancer as well as the molecular processes that drive the development of aggressive prostate cancer and its acquisition of resistance to therapeutic agents. Recent work has shown that the dependence of prostate cancer upon androgenic steroids may derive from the effects of androgens on the tumor’s vascular system that supplies it with oxygen and nutrition. Other work has shown that the lowered oxygen environment that results from therapeutic treatment of a prostate tumor may help drive the development of a more aggressive tumor cell due to the activation of the hypoxic signaling process. Finally, we have discovered a novel male-specific gene, referred to as Protocadherin-PC, that becomes activated in the hormone-deprived environment of a hormone-treated prostate cancer patient and confers a highly aggressive phenotype on the prostate cancer cell through its effects on a critical cell developmental pathway (referred to as Wnt). Protocadherin-PC’s action appears to protect the prostate cancer cell from the effects of hormonal deprivation therapy and confers “stem cell-like” characteristics that further add to the aggressive nature of the cancer cell. These discoveries are being applied to the development of novel gene-specific therapeutics that target protocadherin-PC and the hypoxia-signaling pathway that might eventually be used in the treatment of prostate cancer patients.

Selected Publications

• Anastasiadis, A.G., Vacherot, F., Ghafar, M.A., Benedit, P., Chen, M.-W., Shabsigh, A., Burchardt, M., Chopin, D., Shabsigh, R. and Buttyan, R. (2002) Human hormone refractory prostate cancers can harbor mutations in the O 2 -dependent degradation domain of hypoxia inducible factor-1 a (HIF-1 a ). J. Cancer Res. Clin. Oncol. 128: 358-362.
• Ghafar, M.A., Anastasiadis, A.G., Chen, M.-W., Xie, H., Benson, M.C., Olsson, L.E. and Buttyan, R. (2002) Acute hypoxia increases the aggressive characteristics and survival properties of prostate cancer cells. The Prostate, 54: 58-67.
• Chen, M.-W., Vacherot, F., de la Taille, A., Shen, R., Gil-Diez-de-Medina, S., Chopin, D.K., Friedman, R. and Buttyan, R. (2002) Emergence of protocadherin T6 expression during the acquisition of apoptosis resistance by human prostate cancer cells. Oncogene , 21: 7861-7871.
• Bemis, D.L., Capodice, J.L., Anastasiadis, A., Katz, A.E. and Buttyan, R. (2005) Zyflamend, a unique herbal preparation with non-selective COX inhibitory activity, induces apoptosis in prostate cancer cells that lack COX-2 expression. Nutrition and Cancer , 52: 202-212.
• Yang, X., Chen, M.W., Terry, S., Vacherot, F., Chopin, D., Bemis, D., Kitajewski, J., Benson, M.C., Guo, Y. and Buttyan, R. (2005) A human- and male-specific protocadherin that acts through the wnt signaling pathway to induce neuroendocrine transdifferentiation of prostate cancer cells. Cancer Res . 65: 5263-5271.
• Yang, X., Chen, M.-W., Terry, S., Vacherot, F., Bemis, D.L., Capodice, J., Guo, Y. and Buttyan, R. (2006) Complex regulation of human androgen receptor expression by Wnt signaling in prostate cancer cells. Oncogene , (E-Pub, Feb 13, 2006).