REGULATION OF LIPID SIGNALING PATHWAYS FOR CELL-SURVIVAL AND APOPTOSIS BY BCL-2 IN PROSTATE CARCINOMA-CELLS

Compelling evidence indicates that activation of the JNH/SAPK signalin g pathway is obligatory for apoptosis induction by multiple cell stres ses that activate the sphingomyelin cycle. Moreover, ectopic expressio n of bcl-2 can impair apoptosis signaling by most of the cell stresses that activate the ceramide/JNK pathway. Here we show that enforced ex pression of bcl-2 protects prostate carcinoma cells against the induct ion of apoptosis by exogenous C-2-ceramide. Moreover, enforced bcl-2 e xpression blocked the capacity of C-2-ceramide to activate JNK1, indic ating bcl-2 functions at the level of JNK1 or upstream of JNK1 in the ceramide/JNK pathway. The contribution of bcl-2 to the regulation of t he arachidonate pathway for prostate carcinoma cell survival was also investigated using highly selective inhibitors of arachidonate metabol ism. Our results indicate bcl-2 can protect cells against diminished a vailability of arachidonic acid, 12-HETE, and 15-HETE. Finally, arachi donic acid substantially suppresses the induction of apoptosis by C-2- ceramide, providing evidence for the opposing influences of these lipi d signaling pathways in the mediation of prostate carcinoma cell survi val. These results provide evidence for opposing influences of the cer amide and arachidonate signaling pathways in the mediation of cell dea th and cell survival, respectively, in prostate carcinoma cells and su ggest a dual role for bcl-2 in this context. (C) 1997 Academic Press.