INHIBITION OF CASPASES BY CYTOKINE RESPONSE MODIFIER A BLOCKS ANDROGEN ABLATION-MEDIATED PROSTATE-CANCER CELL-DEATH IN-VIVO

Androgen withdrawal is a major therapeutic modality in the treatment o f prostate cancer, Although tumors initially respond, they subsequentl y relapse, and these recurring tumors are androgen independent, To exa mine possible mechanisms to explain the androgen independence of prost ate cancer, we have expressed cytokine response modifier A (CrmA), a c ompetitive inhibitor of caspases, interleukin 1 beta-converting enzyme -like proteases, which mediate apoptotic cell death, in the human andr ogen-dependent prostate cancer cell line LNCaP, LNCaP cells require an drogens for continuous growth in culture and to form tumors in nude mi ce, The expression of CrmA in LNCaP cells prevented the decreased grow th rate induced by androgen withdrawal in tissue culture. When CrmA-ex pressing LNCaP (LNCaP-CrmA) cells were implanted s.c. in nude mice, th e tumors grew six times faster than parental cells. Androgen ablation by castration before tumor implantation suppressed the ability of cont rol LNCaP cells expressing nonfunctional CrmA mutant (R291T) to form t umors, but LNCaP-CrmA cells formed tumors similar in size to those for med in normal mice, When orchiectomy was performed 10 days after tumor implantation, control LNCaP cells expressing a nonfunctional CrmA mut ant (R291T) regressed, but LNCaP-CrmA tumors continued to grow, Thus, inhibition of caspases prevents androgen withdrawal-induced prostate c ancer cell death, suggesting that caspase activation is normally an im portant part of this process.