文章基本信息

标题：Overcoming cancer cell resistance to Smac mimetic induced apoptosis by modulating cIAP-2 expression
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作者：Sean L. Petersen ; Michael Peyton ; John D. Minna 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：26
页码：11936-11941
DOI：10.1073/pnas.1005667107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Smac mimetics target cancer cells in a TNF{alpha}-dependent manner, partly via proteasome degradation of cellular inhibitor of apoptosis 1 (cIAP1) and cIAP2. Degradation of cIAPs triggers the release of receptor interacting protein kinase (RIPK1) from TNF receptor I (TNFR1) to form a caspase-8 activating complex together with the adaptor protein Fas-associated death domain (FADD). We report here a means through which cancer cells mediate resistance to Smac mimetic/TNF{alpha}-induced apoptosis and corresponding strategies to overcome such resistance. These human cancer cell lines evades Smac mimetic-induced apoptosis by up-regulation of cIAP2, which although initially degraded, rebounds and is refractory to subsequent degradation. cIAP2 is induced by TNF{alpha} via NF-{kappa}B and modulation of the NF-{kappa}B signal renders otherwise resistant cells sensitive to Smac mimetics. In addition, other signaling pathways, including phosphatidyl inositol-3 kinase (PI3K), have the potential to concurrently regulate cIAP2. Using the PI3K inhibitor, LY294002, cIAP2 up-regulation was suppressed and resistance to Smac mimetics-induced apoptosis was also overcome.
关键词：TNFα ; NF-κB ; PI3K ; Caspase-8 ; PRIK1