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Overexpression of cFLIPs inhibits oxaliplatin‐mediated apoptosis through enhanced XIAP stability and Akt activation in human renal cancer cells
Author(s) -
Kim Shin,
Lee TaeJin,
Park JongWook,
Kwon Taeg Kyu
Publication year - 2008
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21905
Subject(s) - xiap , apoptosis , inhibitor of apoptosis , protein kinase b , pi3k/akt/mtor pathway , oxaliplatin , cancer research , chemistry , programmed cell death , microbiology and biotechnology , caspase , biology , cancer , biochemistry , colorectal cancer , genetics
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.