Get access

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

Authors

  • Shin Kim,

    1. Department of Immunology and Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu 700-712, South Korea
    Search for more papers by this author
  • Tae-Jin Lee,

    1. Department of Immunology and Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu 700-712, South Korea
    Search for more papers by this author
  • Jong-Wook Park,

    1. Department of Immunology and Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu 700-712, South Korea
    Search for more papers by this author
  • Taeg Kyu Kwon

    Corresponding author
    1. Department of Immunology and Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu 700-712, South Korea
    • Department of Immunology, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu 700-712, South Korea.
    Search for more papers by this author

  • Shin Kim and Tae-Jin Lee contributed equally this work.

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 cFLIPL 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.

Ancillary