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Inhibition of tumor growth and induction of apoptosis in prostate cancer cell lines by overexpression of tissue inhibitor of matrix metalloproteinase-3

Cancer Gene Therapy volume 17, pages 171–179 (2010)Cite this article

Abstract

The destruction of extracellular matrix by matrix metalloproteinases is a key event in cancer progression. The tissue inhibitors of metalloproteinases can restrain tumor growth by inhibiting these enzymes. We sought to determine whether overexpression of tissue inhibitor of metalloproteinase-3 (TIMP-3) could suppress the malignant phenotype of human prostate cancer cell line PC-3M. Stable overexpression of TIMP-3 inhibited cell proliferation significantly by MTT assay. Both early and late apoptosis were observed in TIMP-3 overexpressing cells, and flow cytometry analysis showed S-phase blocking of the cell cycle. Monolayer invasion assay and transwell invasion assay showed significantly decreased invasive potential in TIMP-3 overexpressing cells compared with control cells. Cell adhesion and motility were also lower after TIMP-3 was overexpressed. In vivo, cells stably overexpressing TIMP-3 completely lost the ability to form tumors after injection into nude mice. Transfection of TIMP-3 into established tumors by electroporation also had a significant antitumor effect. TIMP-3-treated tumor tissues had significant apoptosis by TUNEL assay. These results showed that overexpression of TIMP-3 inhibits invasion and proliferation of prostate cancer cells in vitro and inhibits tumor growth in vivo. The experiments suggest a potential use for TIMP-3 in the gene therapy of prostate cancer.

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Acknowledgements

This work was funded by National Natural Science Foundation of China (No. 30801354) and Jilin Provincial Science & Technology Department (No. 20080154). We thank Professor Frederick William Orr for his critical reading and revising our paper.

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  1. L Zhang and L Zhao: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathophysiology, Prostate Diseases Prevention and Treatment Research Centre, Norman Bethune Medical School, Jilin University, Changchun, China

    L Zhang, L Zhao, D Zhao, G Lin, Y Li, Z Liang & X J Zhao

  2. Emergency Department, China–Japan Union Hospital of Jilin University, Changchun, China

    B Guo

  3. Laboratory for Molecular Enzymology and Engineering, the Ministry of Education (MEE), Jilin University, Changchun, China

    X Fang

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  1. L Zhang
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Correspondence to X J Zhao or X Fang.

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Zhang, L., Zhao, L., Zhao, D. et al. Inhibition of tumor growth and induction of apoptosis in prostate cancer cell lines by overexpression of tissue inhibitor of matrix metalloproteinase-3. Cancer Gene Ther 17, 171–179 (2010). https://doi.org/10.1038/cgt.2009.59

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