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Tumor Necrosis Factor Induces BID Cleavage and Bypasses Antiapoptotic Signals in Prostate Cancer LNCaP Cells¹

Department of Microbiology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908 [G. K., J. P. C., T. V., K. O., B. D. G., M. J. W.]; University of Michigan Medical School, Ann Arbor, Michigan 48109 [G. N.]; and Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [S. S., E. A.]

Survival of cancer cells in response to therapy, immune response, or metastasis depends on interactions between pro- and antiapoptotic signals. Two major 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 signals that act to inhibit the mitochondrial proapoptotic pathway in prostate cancer LNCaP cells. However, it was unclear at what level the pro- and antiapoptotic signals interact in these cells, and it was also unclear whether these signals would inhibit the death receptor pathway. We found that EGF can protect LNCaP cells from apoptosis induced by LY294002 but not from tumor necrosis factor (TNF-)-induced apoptosis. Furthermore, TNF- induced apoptosis under conditions in which Akt was active. Treatment with TNF- resulted in activation of caspase 8 and cleavage of BID, which in turn induced cytochrome c release and caspase 9-dependent activation of effector caspases. Thus, proapoptotic signals induced by both TNF- and LY294002 converge on mitochondria and trigger cytochrome c release. Because EGF can inhibit cytochrome c release induced by LY294002 but not cytochrome c release induced by TNF-, we suggest that the EGF survival mechanism operates on the mitochondrial pathway at a site upstream of cytochrome c release. The ability of TNF- to bypass survival signals from activated EGF receptor and Akt in prostate cancer cells makes death receptor signaling a promising avenue for therapeutic intervention.

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