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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Apoptosis / drug effects*
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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Baculoviral IAP Repeat-Containing 3 Protein
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Base Sequence
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Biomimetic Materials / pharmacology*
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Chromones / pharmacology
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Drug Resistance, Neoplasm* / genetics
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Drug Resistance, Neoplasm* / physiology
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Humans
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I-kappa B Kinase / antagonists & inhibitors
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I-kappa B Kinase / genetics
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Imidazoles / pharmacology
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / metabolism*
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Intracellular Signaling Peptides and Proteins / physiology*
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Mitochondrial Proteins / physiology*
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Morpholines / pharmacology
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NF-kappa B / antagonists & inhibitors
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Quinoxalines / pharmacology
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RNA, Small Interfering / genetics
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Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors
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Receptor-Interacting Protein Serine-Threonine Kinases / genetics
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Tumor Necrosis Factor-alpha / pharmacology
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Ubiquitin-Protein Ligases
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Up-Regulation / drug effects
Substances
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4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline
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Apoptosis Regulatory Proteins
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Chromones
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DIABLO protein, human
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IKBKG protein, human
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Imidazoles
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Inhibitor of Apoptosis Proteins
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Intracellular Signaling Peptides and Proteins
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Mitochondrial Proteins
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Morpholines
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NF-kappa B
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Phosphoinositide-3 Kinase Inhibitors
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Quinoxalines
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RNA, Small Interfering
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Tumor Necrosis Factor-alpha
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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BIRC3 protein, human
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Baculoviral IAP Repeat-Containing 3 Protein
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Ubiquitin-Protein Ligases
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Proto-Oncogene Proteins c-akt
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RIPK1 protein, human
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Receptor-Interacting Protein Serine-Threonine Kinases
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I-kappa B Kinase