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

Abstract

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 (DC-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. DC-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.

Lipid Rafts and Caveolin-1 Are Required for Invadopodia Formation and Extracellular Matrix Degradation by Human Breast Cancer Cells

“…It has been shown that MT1-MMP resides in lipid rafts (38,39) and increased localization of MT1-MMP in lipid rafts enhances invasion of prostate cancer cells (40). Consistent with these reports, the present study found that MT1-MMP is preferentially localized in lipid raft fractions among major invadopodia components.…”

Membrane-type matrix metalloproteinases: expression, roles in metastatic prostate cancer progression and opportunities for drug targeting

“…This cleavage was shown to decrease cell adhesion to purified Ln-10, and to increase transmigration of DU-145 cells through cleaved Ln-10 and thus the basal lamina. Increased invasion mediated by MT1-MMP was also observed by Wang et al [34] . Using cells engineered to overexpress MT1-MMP (namely PC3-LN4), invasion into type-I collagen gels in vitro was observed, through activation of pro-MMP2.…”

HOX transcription factors and the prostate tumor microenvironment

“…MMP-14 differs from other MMPs as it is membrane bound through a transmembrane domain with its catalytic center on the outside of the cell [64] . Its expression in prostate cancer cells is associated with androgen independence [65] and aggressiveness [66] . Prostate tumors primarily metastasize to bone, and MMP-14 has a particularly important role in this process due to HOX transcription factors regulate genes in prostate cancer cells that modify the tumor microenvironment, as well genes in stromal cells that support tumor growth.…”