title: An apoptosis-independent role of SMAC in tumor suppression.
abstract: Reduced expression of the pro-apoptotic protein SMAC (second mitochondria-derived activator of caspase) has been reported to correlate with cancer progression, while its significance and underlying mechanisms are poorly understood. In this study, we investigated the role of SMAC in intestinal tumorigenesis using both human samples and animal models. Decreased SMAC expression was found to correlate with increased cIAP2 expression and higher grades of human colon cancer. In mice, SMAC deficiency significantly increased the incidence and size of colon tumors induced by azoxymethane (AOM)/dextran sulfate sodium salt (DSS), and highly enriched β-catenin hot spot mutations. SMAC deficiency also significantly increased the incidence of spontaneous intestinal polyps in APC(Min/+) mice. Loss of SMAC in mice led to elevated levels of cIAP1 and cIAP2, increased proliferation and activation of the NF-κB p65 subunit in normal and tumor tissues. Unexpectedly, SMAC deficiency had little effect on the incidence of precursor lesions, or apoptosis induced by AOM or DSS, or in established tumors in mice. Furthermore, SMAC knockout enhanced TNFα-mediated NF-κB activation via cIAP2 in HCT 116 colon cancer cells. These results demonstrate an essential and apoptosis-independent function of SMAC in tumor suppression and provide new insights into the biology and targeting of colon cancer.
authors: University of Pittsburgh Cancer Institute, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: W
authors: W
authors: Qiu
authors: H
authors: H
authors: Liu
authors: A
authors: A
authors: Sebastini
authors: Q
authors: Q
authors: Sun
authors: H
authors: H
authors: Wang
authors: L
authors: L
authors: Zhang
authors: J
authors: J
authors: Yu
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D045325:HCT116 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C412403:DIABLO protein, human; C499605:Diablo protein, mouse; D020672:I-kappa B Proteins; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases