Role of XIAP in inhibiting cisplatin-induced caspase activation in non-small cell lung cancer cells: A small molecule Smac mimic sensitizes for chemotherapy-induced apoptosis by enhancing caspase-3 ac

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• 作者：Agnieszka Checinska ; Bas S.J. Hoogel ; Jose A. Rodriguez ; Giuseppe Giaccone ; Frank A.E. Kruyt
• 关键词：Lung cancer ; Cisplatin-based chemotherapy ; XIAP ; Smac
• 刊名：Experimental Cell Research
• 出版年：2007
• 出版时间：1 April 2007
• 年：2007
• 卷：313
• 期：6
• 页码：1215-1224
• 全文大小：757 K

文摘

X-linked IAP (XIAP) suppresses apoptosis by binding to initiator caspase-9 and effector caspases-3 and -7. Smac/DIABLO that is released from mitochondria during apoptosis can relieve its inhibitory activity. Here we investigated the role of XIAP in the previously found obstruction of chemotherapy-induced caspase-9 activation in non-small cell lung cancer (NSCLC) cells. Endogenously expressed XIAP bound active forms of both caspase-9 and caspase-3. However, downregulation of XIAP using shRNA or disruption of XIAP/caspase-9 interaction using a small molecule Smac mimic were unable to significantly induce caspase-9 activity, indicating that despite a strong binding potential of XIAP to caspase-9 it is not a major determinant in blocking caspase-9 in NSCLC cells. Although unable to revert caspase-9 blockage, the Smac mimic was able to enhance cisplatin-induced apoptosis, which was accompanied by increased caspase-3 activity. Additionally, a more detailed analysis of caspase activation in response to cisplatin indicated a reverse order of activation, whereby caspase-3 cleaved caspase-9 yielding an inactive form. Our findings indicate that the use of small molecule Smac mimic, when combined with an apoptotic trigger, may have therapeutic potential for the treatment of NSCLC.