Type 1 insulin-like growth factor regulates MT1-MMP synthesis and tumor invasion via PI 3-kinase/Akt signaling

Oncogene. 2003 Feb 20;22(7):974-82. doi: 10.1038/sj.onc.1206197.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Androstadienes / pharmacology
  • Animals
  • Carcinoma, Lewis Lung / metabolism
  • Carcinoma, Lewis Lung / pathology*
  • Chromones / pharmacology
  • Collagen
  • Drug Combinations
  • Enzyme Induction / drug effects
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Insulin-Like Growth Factor I / pharmacology
  • Insulin-Like Growth Factor I / physiology*
  • Laminin
  • Matrix Metalloproteinase 14
  • Matrix Metalloproteinase 2 / physiology
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases / biosynthesis*
  • Metalloendopeptidases / genetics
  • Mice
  • Morpholines / pharmacology
  • Neoplasm Invasiveness / physiopathology*
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • PTEN Phosphohydrolase
  • Phosphatidylinositol 3-Kinases / physiology*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / physiology
  • Phosphorylation / drug effects
  • Point Mutation
  • Promoter Regions, Genetic
  • Protein Kinases / physiology*
  • Protein Processing, Post-Translational / drug effects
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Proteoglycans
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins*
  • RNA, Messenger / biosynthesis
  • RNA, Neoplasm / biosynthesis
  • Receptor, IGF Type 1 / drug effects
  • Receptor, IGF Type 1 / physiology*
  • Recombinant Fusion Proteins / physiology
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases
  • Tumor Cells, Cultured / metabolism
  • Tumor Cells, Cultured / pathology
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / physiology
  • Wortmannin

Substances

  • Androstadienes
  • Chromones
  • Drug Combinations
  • Enzyme Inhibitors
  • Flavonoids
  • Laminin
  • Mmp14 protein, mouse
  • Morpholines
  • Neoplasm Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Proteoglycans
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • RNA, Neoplasm
  • Recombinant Fusion Proteins
  • Tumor Suppressor Proteins
  • matrigel
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Insulin-Like Growth Factor I
  • Collagen
  • Protein Kinases
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Receptor, IGF Type 1
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 14
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
  • Sirolimus
  • Wortmannin