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Transfection of Smac sensitizes tumor cells to etoposide-induced apoptosis and eradicates established human hepatoma in vivo

Cancer Gene Therapy volume 13, pages 420–427 (2006)Cite this article

Abstract

A major concern in clinical treatment of cancers is resistance of tumors such as hepatocellular carcinoma (HCC) and osteosarcoma to current chemotherapy protocols. Here, we reported that overexpression of second mitochondria-derived activator of caspase (Smac) sensitized osteosarcoma cells and HCC cells in vitro to chemotherapeutic drugs-induced apoptosis. Constitutive expression of Smac resulted in enhanced Bax accumulation on mitochondria upon etoposide stimulation and inhibited Bcl-2-induced antiapoptosis activity. Thus, Smac would sensitize tumor cells to chemotherapeutic drugs in part through promoting Bax translocation to mitochondria and bypassing Bcl-2 block. Moreover, we demonstrated that blockade of Smac expression by antisense smac did not impair etoposide-induced apoptosis; however, p53-induced apoptosis was impaired in smac deficient Saos-2 cell. This suggested Smac might be required in p53-induced apoptosis. Most importantly, complete eradication of HepG2 xenografts in vivo was achieved upon combined therapy with Ad-Smac and 5-Fu. Thus, overexpression of Smac in tumor cells might be a potent strategy for cancer treatment by sensitization of tumor cells to chemotherapeutic drugs.

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Acknowledgements

We thank Dr Xiaodong Wang for providing antibody to Smac and plasmid encoding smac cDNA and Ms Yan Huang and Ms Xiaodong Li for their assistance with the experiments. This work is supported in part by grants from National Natural Science Foundation of China, Ministry of Science and Technology of China (973 program) and Shanghai Commission of Science and Technology. Dr Jian Zhao is an excellent investigator supported by a fellowship award from Ministry of Education of China.

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  1. J Zhao and J Jin: These authors contributed equally to this work.

Authors and Affiliations

  1. International Joint Cancer Institute, E-Institute of Shanghai Universities and Eastern Hospital of Hepatobiliary Surgery, The Second Military Medical University, Shanghai, P.R. China

    J Zhao, J Jin, X Zhang, M Shi, J Dai, M Wu, R Wang & Y Guo

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Correspondence to Y Guo.

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Zhao, J., Jin, J., Zhang, X. et al. Transfection of Smac sensitizes tumor cells to etoposide-induced apoptosis and eradicates established human hepatoma in vivo. Cancer Gene Ther 13, 420–427 (2006). https://doi.org/10.1038/sj.cgt.7700910

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