Carcinogenesis Advance Access originally published online on July 10, 2008
Carcinogenesis 2008 29(8):1655-1664; doi:10.1093/carcin/bgn159
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Impaired tyrosine phosphorylation of membrane type 1-matrix metalloproteinase reduces tumor cell proliferation in three-dimensional matrices and abrogates tumor growth in mice
1 Laboratoire de Médecine Moléculaire, Centre de Cancérologie Charles-Bruneau, CHU Sainte-Justine, 3175 Chemin Côte-Ste-Catherine, Montréal, Québec, Canada H3T 1C5
2 Département de Pathologie, CHU Sainte-Justine, 3175 Chemin Côte-Ste-Catherine, Montréal, Québec, Canada H3T 1C5
3 Centre de Recherches Biomédicales (Biomed), Université du Québec à Montréal, C.P. 8888, succursale Centre-Ville, Montréal, Québec, Canada H3C 3P8
* To whom correspondence should be addressed. Laboratoire de Médecine Moléculaire Ste-Justine-UQAM, Centre de cancérologie Charles-Bruneau, 3175, Chemin Côte-Ste-Catherine, Montréal, Québec, Canada H3T 1C5. Tel: +1 514 345 2366; Fax: +1 514 345 2359; Email: molmed{at}recherche-ste-justine.qc.ca
Pericellular proteolysis of the extracellular matrix by membrane type 1-matrix metalloproteinase (MT1-MMP) confers tumor cells with the ability to proliferate within three-dimensional (3D) matrices and sustains tumor growth in mice. In this study, we show that in addition to its matrix-degrading activity, phosphorylation of MT1-MMP on its unique tyrosine residue located within its cytoplasmic sequence (Tyr573) may also participate to these processes. Fibrosarcoma cells expressing a proteolytically active but non-phosphorylable mutant of MT1-MMP showed a markedly reduced proliferation rate when embedded within 3D type I collagen matrices, this antiproliferative effect being correlated with arrest in the G0/G1 phase of the cell cycle. Impaired tyrosine phosphorylation of MT1-MMP also inhibits anchorage-independent growth of HT-1080 cells in soft agar as well as their invasion of collagen barriers, two prominent attributes of tumor cells, suggesting a broad inhibitory effect of the MT1-MMP mutant on tumorigenesis. Accordingly, whereas HT-1080 cells formed well-vascularized tumors containing tyrosine-phosphorylated MT1-MMP, tumor growth was completely abolished by expression of the non-phosphorylable MT1-MMP mutant. These findings thus indicate a close co-operation between the matrix-degrading activity of MT1-MMP and tyrosine phosphorylation of its intracellular domain for tumor cell invasion and proliferation and suggest that the targeting of the intracellular signaling pathways leading to tyrosine phosphorylation of MT1-MMP may represent an unexpected alternative strategy for the inhibition of this enzyme.
Abbreviations: BB, binding buffer; cDNA, complementary DNA; 2D, two dimensional; 3D, three dimensional; ECM, extracellular matrix; FBS, fetal bovine serum; FITC, fluorescein isothiocyanate; HPS, hematoxylin, phloxin and saffron; MEM, minimum essential medium; MMP, matrix metalloproteinases; MT1-MMP, membrane type 1-matrix metalloproteinase; PBS, phosphatebuffered saline; PI, propidium iodide; TIMP, tissue inhibitor of matrix metalloproteinases
Received March 24, 2008; revised June 27, 2008; accepted July 2, 2008.
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