Androgenic and Anti-Androgenic regulation of c-FLIP in Prostate Cancer

Kristin Raclaw

The transition of prostate cancer from an androgen-dependent tumor to a hormone-depletion-independent tumor is dependent upon a number of alterations to cell signaling pathways, including those that regulate apoptosis (programmed cell death) and cellular proliferation. My work aims to examine how treatment of prostate cancer cells with androgens and clinically relevant antiandrogens affects the expression of the cellular Fas/FasL-associated death domain protein-like inhibitory protein (c-FLIP). c-FLIP inhibits the activation of procaspase-8, thus preventing pro-apoptotic signaling mediated by death receptors at the cell surface. Research from other institutions and our laboratory indicates that androgens induce the expression of the anti-apoptotic c-FLIP gene via the activation of the androgen receptor, a member of the steroid hormone family of transcription factors and a critical molecule in the etiology of prostate cancer. At the protein level, c-FLIP expression increases following androgen treatment in androgen-dependent cells, while androgen-independent cells exhibit no change in c-FLIP protein levels following androgen treatment. This suggests that mechanisms of regulating the expression of c-FLIP, and potentially other anti-apoptotic proteins might become altered during the transition to androgen-independence thus promoting the growth of the tumor. Additionally, treatment of prostate cancer cells with the antiandrogen Bicalutamide (Casodex) decreases the expression of c-FLIP protein without affecting the expression of c-FLIP mRNA. This independent effect on protein expression suggests a novel mechanism for Bicalutamide activity in prostate cancer cells that is not reliant upon its activity as competitive binder of androgens on the androgen receptor. Current work aims to describe the mechanism through which Bicalutamide independently downregulates c-FLIP protein, possibly through increasing the rate of proteasomal degradation of the protein. Also, describing the functional effects of c-FLIP downregulation affects rates of apoptosis and proliferation of prostate cancer cells is of particular interest as this novel activity of Bicalutamide might be utilized to further understand the transition to hormone-depletion-independent disease as well as being exploited as a potential target in prostate cancer therapy.