Abstract
The membrane type 1 matrix metalloproteinase (MT1-MMP) has been identified as a major activator of MMP-2 - a process involving the formation of a trimolecular complex with TIMP-2. We previously identified the IGF-I receptor as a positive regulator of MMP-2 synthesis. Here, we investigated the role of IGF-IR in the regulation of MT1-MMP. Highly invasive Lewis lung carcinoma subline H-59 cells express MT1-MMP and utilize it to activate their major extracellular matrix degrading proteinase-MMP-2. These cells were transiently transfected with a plasmid vector expressing a luciferase reporter gene downstream of the mouse MT1-MMP promoter. IGF-I treatment increased luciferase activity in the transfected cells by up to 10-fold and augmented endogenous MT1-MMP mRNA and protein synthesis by up to 2-3-fold, relative to controls. MT1-MMP induction and invasion were blocked by the PI 3-kinase inhibitors LY294002 and wortmannin and by rapamycin, but not by the MEK inhibitor PD98059. Overexpression of a dominant negative Akt mutant or of the tumor suppressor phosphatase and tensin homologue, PTEN, in these cells also caused a significant reduction in MT1-MMP expression and invasion. The results demonstrate that IGF-IR controls tumor cell invasion by coordinately regulating MMP-2 expression and its MT1-MMP-mediated activation and identify PI 3-kinase/Akt/mTOR signaling as critical to this regulation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Substitution
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Androstadienes / pharmacology
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Animals
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Carcinoma, Lewis Lung / metabolism
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Carcinoma, Lewis Lung / pathology*
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Chromones / pharmacology
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Collagen
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Drug Combinations
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Enzyme Induction / drug effects
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects
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Insulin-Like Growth Factor I / pharmacology
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Insulin-Like Growth Factor I / physiology*
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Laminin
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Matrix Metalloproteinase 14
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Matrix Metalloproteinase 2 / physiology
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Matrix Metalloproteinases, Membrane-Associated
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Metalloendopeptidases / biosynthesis*
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Metalloendopeptidases / genetics
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Mice
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Morpholines / pharmacology
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Neoplasm Invasiveness / physiopathology*
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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PTEN Phosphohydrolase
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Phosphatidylinositol 3-Kinases / physiology*
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / physiology
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Phosphorylation / drug effects
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Point Mutation
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Promoter Regions, Genetic
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Protein Kinases / physiology*
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Protein Processing, Post-Translational / drug effects
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Protein-Serine-Threonine Kinases / genetics
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Protein-Serine-Threonine Kinases / physiology*
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Proteoglycans
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins*
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RNA, Messenger / biosynthesis
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RNA, Neoplasm / biosynthesis
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Receptor, IGF Type 1 / drug effects
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Receptor, IGF Type 1 / physiology*
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Recombinant Fusion Proteins / physiology
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Signal Transduction / drug effects*
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Signal Transduction / physiology
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases
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Tumor Cells, Cultured / metabolism
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Tumor Cells, Cultured / pathology
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology
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Wortmannin
Substances
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Androstadienes
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Chromones
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Drug Combinations
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Enzyme Inhibitors
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Flavonoids
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Laminin
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Mmp14 protein, mouse
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Morpholines
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Neoplasm Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Proteoglycans
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Proto-Oncogene Proteins
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RNA, Messenger
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RNA, Neoplasm
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Recombinant Fusion Proteins
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Tumor Suppressor Proteins
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matrigel
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Insulin-Like Growth Factor I
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Collagen
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Protein Kinases
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TOR Serine-Threonine Kinases
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mTOR protein, mouse
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Receptor, IGF Type 1
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Protein-Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase
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Matrix Metalloproteinases, Membrane-Associated
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Metalloendopeptidases
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Matrix Metalloproteinase 2
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Matrix Metalloproteinase 14
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Sirolimus
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Wortmannin