Inhibition of tumor growth and induction of apoptosis in prostate cancer cell lines by overexpression of tissue inhibitor of matrix metalloproteinase-3.
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.
Department of Pathophysiology, Prostate Diseases Prevention and Treatment Research Centre, Norman Bethune Medical School, Jilin University, Changchun, China.
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Zhang
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Zhao
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Zhao
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Lin
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Guo
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Li
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Liang
X J
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Zhao
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Fang
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D015316:Genetic Therapy; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D019717:Tissue Inhibitor of Metalloproteinase-3