Cellular cholesterol regulates MT1 MMP dependent activation of MMP 2 via MEK-1 in HT1080 fibrosarcoma cells

FEBS Lett. 2004 May 21;566(1-3):65-70. doi: 10.1016/j.febslet.2004.04.040.

Abstract

Unstimulated human fibrosarcoma cells (HT1080) constitutively secrete matrix metalloproteinase 2 (MMP 2) as a proenzyme requiring proteolytic cleavage by membrane type-1 MMP (MT1 MMP) for activation. Physiological and pharmacological stimuli induce clustering of MT1 MMP/tissue inhibitor of MMP 2 "receptors", promoting binding and activation of MMP 2. We now report that cholesterol depleted HT1080 cells accumulated MT1 MMP on the cell surface and activated MMP 2. A specific inhibitor of mitogen activated protein kinase kinase 1/2 inhibited both MMP 2 activation and extracellular signal-related kinase phosphorylation induced by cholesterol depletion. Our data indicate that the cholesterol content of unstimulated cells is critical for secretion of MMP 2 as an inactive zymogen and control of pericellular proteolysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Membrane / enzymology
  • Cholesterol / deficiency*
  • Cholesterol / metabolism
  • Cholesterol / pharmacology
  • Cyclodextrins / antagonists & inhibitors
  • Cyclodextrins / pharmacology
  • Enzyme Activation / drug effects
  • Fibrosarcoma / enzymology*
  • Fibrosarcoma / metabolism
  • Humans
  • MAP Kinase Kinase 1
  • MAP Kinase Signaling System
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases / metabolism*
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation
  • Protease Inhibitors / pharmacology
  • Tissue Inhibitor of Metalloproteinase-2 / pharmacology
  • beta-Cyclodextrins*

Substances

  • Cyclodextrins
  • Matrix Metalloproteinase Inhibitors
  • Protease Inhibitors
  • beta-Cyclodextrins
  • methyl-beta-cyclodextrin
  • Tissue Inhibitor of Metalloproteinase-2
  • Cholesterol
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • Mitogen-Activated Protein Kinase Kinases
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • Matrix Metalloproteinase 2