Overexpression of cFLIPs inhibits oxaliplatin-mediated apoptosis through enhanced XIAP stability and Akt activation in human renal cancer cells

✍ Scribed by Shin Kim; Tae-Jin Lee; Jong-Wook Park; Taeg Kyu Kwon

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 331 KB
• Volume: 105
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.21905

✦ Synopsis

Abstract

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‐γ1 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. © 2008 Wiley‐Liss, Inc.