title: Tissue inhibitor of metalloproteinase-1 stimulates proliferation of human cancer cells by inhibiting a metalloproteinase.
abstract: TIMP-1, an approximately 30 kDa glycosylated protein found predominantly in extracellular compartments, is involved in the regulation of a variety of developmental, remodelling, and pathological processes. One function of TIMP-1 is to inhibit certain members of a group of extracellular and cell surface enzymes known collectively as metalloproteinases (MP). These include the matrix metalloproteinases and the adamalysin-like disintegrin and metalloproteinases (ADAMs). Additional activities of TIMP-1 include potentiating the activity of erythroid precursors and stimulating proliferation of certain cancer cell lines. Published evidence suggests that the apparent proliferative action of TIMP-1 is independent of its MP-inhibitory activity; however, reports of a cell surface receptor for TIMP-1 have not been confirmed. We have utilised a baculovirus-based system to produce TIMP-1. Data presented here show that TIMP-1 and synthetic hydroxamate (GM6001) MP inhibitors stimulate proliferation and metabolic activity of MDA-MB-435 cancer cells with similar kinetics. An inactive hydroxamate derivative was ineffective. The TIMP-1-induced increase in proliferation and metabolic activity was not the consequence of the inhibition of apoptosis by TIMP-1 in the serum-free medium. These data taken together imply that the mechanism by which TIMP-1 enhances cell growth depends on its ability to inhibit a metalloproteinase, rather than to stimulate a cell surface receptor by a process independent of its MP-inhibitory activity. Inhibitors of extracellular regulated kinase (U0126) and p38 (SB203580), and to a lesser extent the phosphatidylinositol-3-kinase inhibitor LY294002, suppressed the action of TIMP-1. Assays for ERK1/2 and p38 showed that both were activated by TIMP-1 and GM6001. Mechanisms by which TIMP-1 might act to stimulate cell proliferation are described.
authors.affiliation: The Graduate Program in Microbiology and Molecular Genetics, Department of Cell Biology and Neuroscience, Rutgers University, Nelson Laboratories, 604 Allison Road, Piscataway, NJ 08854, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Porter
authors.forename: S
authors.initials: S
authors.lastname: Shen
authors.forename: D T
authors.initials: DT
authors.lastname: Denhardt
mesh_terms: D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects* / Q000502:physiology*; D004151:Dipeptides / Q000494:pharmacology*; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D045726:Metalloproteases; D008666:Metalloendopeptidases