Overexpression of cFLIPs Inhibits Oxaliplatin-Mediated Apoptosis Through Enhanced XIAP Stability and Akt Activation in Human Renal Cancer Cells

cFLIP inhibits caspase 8 recruitment and processing at the death-inducing signaling complex (DISC), which is known to inhibits apoptosis mediated by death receptors such as Fas and death receptor 5 (DR5) as well as apoptosis mediated by anticancer therapeutic drugs. We observed that oxaliplatin induced apoptosis, the activation of DEVDase activity, DNA fragmentation, and cleavage of PLC-gamma 1 and degradation of XIAP protein in dose-dependent manners, which was prevented by pretreatment with z-VAD or NAC, suggesting that oxaliplatin-induced apoptosis was mediated by caspase- or reactive oxygen species (ROS)-dependent pathways. Furthermore, ectopic expression of cFLIPs potently attenuated oxaliplatin-induced apoptosis, whereas cFLIP(L) had less effect. Interestingly, we found that the protein level of XIAP was sustained in oxaliplatin-treated cFLIPs overexpressing cell, which was caused by the increased XIAP protein stability and that the phospho-Akt level was high compared to vector-transfected cell. The increased XIAP protein stability was lessened by PI3K inhibitor LY294002 treatment in cFLIPs overexpressing cells. Thus, our findings imply that the anti-apoptotic functions of cFLIPs may be attributed to inhibit oxaliplatin-induced apoptosis through the sustained XIAP protein level and Akt activation. J. Cell. Biochem. 105: 971-979, 2008. (C) 2008 Wiley-Liss, Inc.