An apoptosis-independent role of SMAC in tumor suppression
1University of Pittsburgh Cancer Institute, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.
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.
Insights
Second mitochondria-derived activator of caspase (SMAC) deficiency promotes colon cancer by increasing proliferation and NF-κB activation, independent of apoptosis. This highlights SMAC
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Research
Background:
- Reduced expression of the pro-apoptotic protein SMAC (second mitochondria-derived activator of caspase) is linked to cancer progression.
- The precise role and mechanisms of SMAC in intestinal tumorigenesis remain unclear.
Purpose of the Study:
- To investigate the function of SMAC in intestinal tumorigenesis using human samples and animal models.
- To elucidate the molecular mechanisms underlying SMAC's role in colon cancer development.
Main Methods:
- Analysis of human colon cancer tissues for SMAC and cIAP2 expression.
- Utilized azoxymethane (AOM)/dextran sulfate sodium salt (DSS) induced and APC(Min/+) mouse models for intestinal tumorigenesis.
- Assessed proliferation, apoptosis, NF-κB activation, and TNFα-mediated signaling in SMAC-deficient models and HCT 116 cells.
Main Results:
- Decreased SMAC expression correlated with increased cIAP2 and higher human colon cancer grades.
- SMAC deficiency in mice increased colon tumor incidence/size, β-catenin mutations, and spontaneous polyps.
- Loss of SMAC elevated cIAP1/cIAP2, enhanced NF-κB p65 activation, and boosted TNFα-induced NF-κB signaling via cIAP2.
Conclusions:
- SMAC functions as a tumor suppressor in the intestine through an apoptosis-independent mechanism.
- SMAC deficiency promotes colon cancer via increased proliferation and NF-κB pathway activation.
- Findings offer novel insights into colon cancer biology and potential therapeutic targeting of SMAC.
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