title: Overcoming cancer cell resistance to Smac mimetic induced apoptosis by modulating cIAP-2 expression.
abstract: Smac mimetics target cancer cells in a TNFalpha-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/TNFalpha-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 TNFalpha via NF-kappaB and modulation of the NF-kappaB 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.
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry and Hamon Center for Therapeutic Oncology Research and Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Sean L
authors.initials: SL
authors.lastname: Petersen
authors.forename: Michael
authors.initials: M
authors.lastname: Peyton
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001483:Base Sequence; D040761:Biomimetic Materials / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics; D007093:Imidazoles / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011810:Quinoxalines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D051017:Apoptosis Regulatory Proteins; D002867:Chromones; C412403:DIABLO protein, human; C491731:IKBKG protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009025:Morpholines; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase