FLIP-ping out: death receptor signaling in the prostate

Prostate cancer is a leading cause of cancer related death. The growth of normal prostate epithelial cells is under the tight control of various growth factors, most notably androgens, such that castration leads to apoptosis of this cell population. Androgen-depletion has a similar effect on prostate cancers; however, following initial regression tumors often return in an androgen-depletion independent form that is frequently lethal. Thus, castration induced prostate regression in rodents has been a valuable model for identifying cell signaling pathways that control the proliferation and apoptosis of both normal and neoplastic prostate epithelial cells. For example, studies of normal prostate regression demonstrated the critical role of paracrine (stromally produced) transforming growth factor-beta. This review examines the role of the TNF-family death receptors and caspases-8 and -10 in prostate epithelial cell death. There is significant evidence that expression of the caspase-8 inhibitor FLIP (FLICE-like inhibitory protein) is androgen regulated and that this protein is one of the key regulators of androgen withdrawal induced cell death. However, it is not yet known which of the death receptor pathways is required for prostate apoptosis in vivo, and this remains an active topic of research.