Journal of Andrology Testis Workshop 2009
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Published-Ahead-of-Print January 8, 2009, DOI:10.2164/jandrol.108.006494
Journal of Andrology, Vol. 30, No. 3, May/June 2009
Copyright © American Society of Andrology
DOI: 10.2164/jandrol.108.006494

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Increased Aggressiveness of Human Prostate PC-3 Tumor Cells Expressing Cell Surface Localized Membrane Type-1 Matrix Metalloproteinase (MT1-MMP)

XING WANG*, MICHAEL J. WILSON{dagger},{ddagger},§,¶, JOEL W. SLATON{ddagger},§,¶, AKHOURI A. SINHA§,||,¶, STEPHEN L. EWING{dagger},¶ AND DUANQING PEI*,§

From the * Department of Pharmacology; the {dagger} Department of Laboratory Medicine and Pathology; the {ddagger} Department of Urologic Surgery; the § Masonic Comprehensive Cancer Center; and the || Department of Genetics, Cell Biology, and Development, University of Minnesota; and the Minneapolis VA Medical Center, Minneapolis, Minnesota.

Correspondence to: Dr Michael J. Wilson, Research Service, Minneapolis VA Medical Center, One Veterans Drive, Minneapolis, MN 55417 (e-mail: Wilso042{at}umn.edu).


Membrane type-1 matrix metalloproteinase (MT1-MMP) is a multidomain transmembrane endopeptidase with a major role in physiological and pathological processes through proteolysis of extracellular matrix and other pericellular proteins. We examined cell surface function of MT1-MMP in PC-3 human prostate tumor cells selected for metastasis in nude mice (PC-3-LN4), or transfected with the full-length wild-type (WT) MT1-MMP or with the mutant form lacking the cytoplasmic tail ({Delta}C-MT1-MMP). Enhanced cell surface MT1-MMP was determined by fluorescence-activated cell sorting analysis and evidenced mechanistically by increased activation of proMMP-2 and invasion into type-I collagen gels. PC-3 cells overexpressing MT1-MMP grew faster than mock-transfected control cells subcutaneously in nude mice. MT1-MMP localized in caveolae, as judged by immunofluorescence microscopy and sucrose-gradient, detergent-resistant cell fractionation. {Delta}C-MT1-MMP was strongly associated with caveolae, whereas the WT form was present in both caveolae and noncaveolae fractions. The role of plasma membrane MT1-MMP was supported by localization of MT1-MMP by immunofluorescence microscopy at the cell surface of tumor cells in primary prostate cancers. Increased plasma membrane localization of MT1-MMP, either in caveolae or in other lipid raft structures, is a mechanism to localize this proteinase in contact with extracellular matrix and other pericellular proteins, the cleavage of which can facilitate prostate cancer cell invasion and metastasis.

     Key words: Cancer, matrix metalloproteinase type-1, MMP-14, tumor cell invasion, caveolae, type I collagen




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