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 APCMin/+ 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.
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Abbreviations
- SMAC:
-
second mitochondria-derived activator of caspases
- IAPs:
-
inhibitors of apoptosis proteins
- BrdU:
-
5-bromodeoxyuridine
- TUNEL:
-
terminal deoxynucleotidyl transferase–mediated deoxyuridinetriphosphate nick end labeling
- WT:
-
wild type
- KO:
-
knockout
- AOM:
-
azoxymethane
- DSS:
-
dextran sulfate sodium salt
- ACF:
-
aberrant crypt foci
- NSAID:
-
nonsteroidal anti-inflammatory drugs
- NF-κB:
-
nuclear factor kappa-light-chain-enhancer of activated B cells
- GSK-3β:
-
glycogen synthase kinase 3 beta
- TRAIL:
-
tumor necrosis factor-related apoptosis inducing ligand
- TNFα:
-
tumor necrosis factor alpha
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Acknowledgements
We thank Monica E Buchanan, Matthew F Brown and other members of Zhang and Yu labs for helpful discussion and critical reading, and Laurice A Vance-Carr for editorial assistance. This work is supported in part by NIH grants CA129829, UO1-DK085570, American Cancer Society grant RGS-10-124-01-CCE and FAMRI (JY), NIH grants CA106348, CA121105, and American Cancer Society grant RSG-07-156-01-CNE (LZ). This project used the UPCI shared glassware, animal, and cell and tissue imaging facilities that were supported in part by award P30CA047904.
Author contributions: WQ, HL, AS and QS performed the experiments and analyzed the data. HW analyzed the data. WQ, LZ and JY designed the experiments, analyzed the data and wrote the paper.
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Qiu, W., Liu, H., Sebastini, A. et al. An apoptosis-independent role of SMAC in tumor suppression. Oncogene 32, 2380–2389 (2013). https://doi.org/10.1038/onc.2012.265
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DOI: https://doi.org/10.1038/onc.2012.265
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