Overcoming cancer cell resistance to Smac mimetic induced apoptosis by modulating cIAP-2 expression

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 26; pp. 11936 - 11941
• Main Authors: Petersen, Sean L., Peyton, Michael, Minna, John D., Wang, Xiaodong
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29-06-2010; National Acad Sciences
• Subjects: Antibodies; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Baculoviral IAP Repeat-Containing 3 Protein; Base Sequence; Biological Sciences; Biomimetic Materials - pharmacology; Cancer; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell death; Cell Line, Tumor; Cell lines; Cells; Chromones - pharmacology; Drug Resistance, Neoplasm - genetics; Drug Resistance, Neoplasm - physiology; Gene expression; Humans; I-kappa B Kinase - antagonists & inhibitors; I-kappa B Kinase - genetics; Imidazoles - pharmacology; Inhibitor of Apoptosis Proteins - genetics; Inhibitor of Apoptosis Proteins - metabolism; Intracellular Signaling Peptides and Proteins - physiology; Kinases; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mitochondrial Proteins - physiology; Morpholines - pharmacology; NF-kappa B - antagonists & inhibitors; Oncology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphorylation; Proteases; Proteins; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Quinoxalines - pharmacology; Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors; Receptor-Interacting Protein Serine-Threonine Kinases - genetics; Receptors; RNA, Small Interfering - genetics; Small interfering RNA; Tumor Necrosis Factor-alpha - pharmacology; Ubiquitin-Protein Ligases; Up regulation; Up-Regulation - drug effects; Western blotting
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1005667107

Smac mimetics target cancer cells in a TNFα-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/TNFα-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 TNFα via NF-κB and modulation of the NF-κB 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, dAP2 up-regulation was suppressed and resistance to Smac mimetics-induced apoptosis was also overcome.