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Published on: August 21, 2013
Over-expression of Smac promotes TRAIL-induced cell death in human hepatocellular carcinoma
Hiroshi Okano1, Katsuya Shiraki, Hidekazu Inoue
1First Department of Internal Medicine, Mie University School of Medicine, Tsu 514-8507, Japan.
Abstract:
The second mitochondria-derived activator of caspase, Smac, is an apoptosis-related protein. Smac releases inhibition of the IAP family from caspase-3 to induce apoptosis. Smac is expressed in some malignant tumor cells and is released from mitochondria into the cytosol after death receptor stimulation to promote apoptosis of tumor cells. In this study, we found down-regulated Smac protein expression in hepatocellular carcinoma (HCC) tissues, compared to that in non-tumor hepatic tissues. Simultaneously, caspase-3 expression also decreased in HCC tissues. HCC cell lines did not undergo apoptosis after TRAIL stimulation, although Smac was expressed in these HCC cells. Ectopic Smac alone did not induce cell death, but could sensitize HCC cells to TRAIL stimulation. With over-expression of Smac in HCC cells, TRAIL induced by 10% HCC cell death. The role of Smac in apoptosis signaling pathway in HCC cells warrants further study.
Insights
Down-regulated Smac protein expression was found in hepatocellular carcinoma (HCC) tissues. Over-expressing Smac sensitized HCC cells to TRAIL-induced apoptosis, suggesting Smac
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Research
Background:
- Smac (second mitochondria-derived activator of caspase) is an apoptosis-related protein that promotes cancer cell death.
- Smac normally inhibits inhibitors of apoptosis proteins (IAPs), thereby enabling caspase-3 activation and apoptosis.
- Its role in hepatocellular carcinoma (HCC) remains to be fully elucidated.
Purpose of the Study:
- To investigate the expression levels of Smac in HCC tissues.
- To determine the functional role of Smac in HCC cell apoptosis, particularly in response to TRAIL stimulation.
Main Methods:
- Comparative analysis of Smac and caspase-3 protein expression in HCC tissues versus non-tumor hepatic tissues.
- Assessment of apoptosis induction in HCC cell lines following TRAIL stimulation with and without Smac manipulation (ectopic expression/over-expression).
Main Results:
- Smac protein expression was significantly down-regulated in HCC tissues compared to non-tumor tissues.
- Caspase-3 expression was also decreased in HCC tissues.
- HCC cell lines did not undergo apoptosis upon TRAIL stimulation alone, despite Smac expression.
- Ectopic Smac expression alone did not induce cell death but sensitized HCC cells to TRAIL.
- Over-expression of Smac in HCC cells led to approximately 10% cell death upon TRAIL induction.
Conclusions:
- Smac expression is reduced in hepatocellular carcinoma.
- Smac plays a role in sensitizing HCC cells to TRAIL-induced apoptosis, although it does not induce cell death independently.
- Further research is needed to fully understand Smac's function in the HCC apoptosis signaling pathway.
