An apoptosis-independent role of SMAC in tumor suppression Journal Article

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Authors: Qiu, W; Liu, H; Sebastini, A.; Sun, Q.; Wang, H; Zhang, L; Yu, J
Article 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 beta-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-kappaB 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 TNFalpha-mediated NF-kappaB 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.
Journal Title: Oncogene
Volume: 32
Issue: 19
ISSN: 1476-5594; 0950-9232
Publisher: Unknown  
Journal Place: England
Date Published: 2013
Start Page: 2380
End Page: 2389
Language: eng
DOI/URL:

10.1038/onc.2012.265
Notes: LR: 20141015; GR: CA106348/CA/NCI NIH HHS/United States; GR: CA121105/CA/NCI NIH HHS/United States; GR: CA129829/CA/NCI NIH HHS/United States; GR: P30CA047904/CA/NCI NIH HHS/United States; GR: R01 CA106348/CA/NCI NIH HHS/United States; GR: R01 CA121105/CA/NCI NIH HHS/United States; GR: R01 CA129829/CA/NCI NIH HHS/United States; GR: U01 DK085570/DK/NIDDK NIH HHS/United States; GR: UO1-DK085570/DK/NIDDK NIH HHS/United States; JID: 8711562; 0 (BIRC3 protein, human); 0 (Carrier Proteins); 0 (DIABLO protein, human); 0 (Diablo protein, mouse); 0 (I-kappa B Proteins); 0 (Inhibitor of Apoptosis Proteins); 0 (Intracellular Signaling Peptides and Proteins); 0 (Mitochondrial Proteins); 0 (NF-kappa B); 139874-52-5 (NF-kappaB inhibitor alpha); NIHMS494889; OID: NLM: NIHMS494889; OID: NLM: PMC3751796; 2012/07/02 [aheadofprint]; ppublish