PTEN sensitizes prostate cancer cells to death receptor-mediated and drug-induced apoptosis through a FADD-dependent pathway

摘要: The PTEN tumor suppressor is frequently mutated in human tumors. Loss of function associated with constitutive survival signaling through the phosphatidylinositol-3 kinase/Akt pathway. Therefore, we asked if reconstitution would lead to reversal resistance apoptosis prostate cancer cells. Adenovirus-mediated expression completely suppressed Akt activation LNCaP cells and enhanced induced by a broad range apoptotic stimuli. sensitized death receptor-mediated necrosis factor, anti-Fas antibody, TRAIL. also non-receptor mediated kinase inhibitor staurosporine chemotherapeutic agents mitoxantrone etoposide. PTEN-mediated was accompanied caspase-3 caspase-8 inhibited specificity caspase Z-VAD-fmk. Bcl-2 overexpression blocked apoptosis. Lipid phosphatase activity required for as G129E mutant selectively deficient lipid unable sensitize involves FADD-dependent pathway both drug-induced coexpression dominant negative FADD Since receptor signaling, mediates caspase-8, which turn cleaves BID, since activated apoptosis, examined BID cleavage facilitated after treatment low doses mitoxantrone. FADD. Taken together, these data are consistent hypothesis that promotes facilitating