Tumor necrosis factor alpha induces BID cleavage and bypasses antiapoptotic signals in prostate cancer LNCaP cells

Survival of cancer cells in response to therapy, immune response, or metast asis depends on interactions between pro- and antiapoptotic signals. Two ma jor proapoptotic pathways have been described: (a) a death receptor pathway ; and (b) a mitochondrial pathway. We reported previously that Akt and the epidermal growth factor (EGF) receptor send separate, redundant survival si gnals that act to inhibit the mitochondrial proapoptotic pathway in prostat e cancer LNCaP cells. However, it was unclear at what level the pro- and an tiapoptotic signals interact in these cells, and it was also unclear whethe r these signals would inhibit the death receptor pathway. We found that EGF can protect LNCaP cells from apoptosis induced by LY294002 but not from tu mor necrosis factor alpha (TNF-alpha)-induced apoptosis. Furthermore, TNF-a lpha induced apoptosis under conditions in which Akt was active. Treatment with TNF-alpha resulted in activation of caspase 8 and cleavage of BID, whi ch in turn induced cytochrome c release and caspase 9-dependent activation of effector caspases, Thus, proapoptotic signals induced by both TNF-alpha and LY294002 converge on mitochondria and trigger cytochrome c release. Bec ause EGF can inhibit cytochrome c release induced by LY294002 but not cytoc hrome c release induced by TNF-alpha, we suggest that the EGF survival mech anism operates on the mitochondrial pathway at a site upstream of cytochrom e c release. The ability of TNF-LU to bypass survival signals from activate d EGF receptor and Akt in prostate cancer cells makes death receptor signal ing a promising avenue for therapeutic intervention.