Regulation of TRAIL-Mediated Apoptosis in Prostate Cancer by Overexpression in XIAP

摘要

The failure to eradicate advanced prostate cancer that is resistant to conventional therapies, such as chemo and hormonal therapies, has led to the exploration of novel therapeutic applications such as immunotherapy. One form of immunotherapy is to generate anti-tumor cytotoxic lymphocytes that can recognize and eradicate resistant tumor cells. Cytotoxic lymphocytes mediate their killing by various mechanisms including the perforin granzyme pathway and by members of the TNF-alpha superfamily. Among the TNF-alpha superfamily, TRAIL has been shown to be selectively cytotoxic to cancer cells and poorly cytotoxic to normal cells and is, therefore, considered as a good candidate for prostate cancer therapy. However, the development of drug/hormonal resistant prostate cancer results in the development of tumor cells resistant to immune killer cells and, indeed, prostate cancer cell lines have been shown to be relatively resistant to TRAIL-induced apoptosis. Resistance is under the regulation of apoptotic regulatory gene products in the cancer cells. We have demonstrated that prostate cancer cells resistant to TRAIL are due in large part to the overexpression of the anti-apoptotic gene product, XIAP and Bc1(sub -xL), both of which are under the regulation of constitutive NF-kB. Inhibition of NF-kB or either XIAP or Bc1(sub-xL) expression results in the reversal of resistant tumor cells and sensitivity to TRAIL-induced apoptosis. This proposal investigates the role of XIAP in resistance to TRAIL and investigates the underlying mechanisms of the regulation of XIAP expression in prostate cancer cells. We have proposed to investigate (1) The role of XIAP in protecting prostate cancer cells from TRAIL-mediated apoptosis, (2) The regulation of XIAP by NF-kB and NF-kB regulation by XIAP, and (3) The role of endogenous TNF-alpha and IL-6 in the regulation of XIAP and resistance of tumor cells to TRAIL- induced apoptosis.