Necrosis induction in glioblastoma cells reveals a new "bioswitch" function for the MT1-MMP/G6PT signaling axis in proMMP-2 activation versus cell death decision

Neoplasia. 2007 Apr;9(4):332-40. doi: 10.1593/neo.07142.


Cytoskeleton disorganization is an early step in the activation process of matrix metalloproteinase 2 (MMP-2) by membrane type 1 MMP (MT1-MMP) but is also associated with endoplasmic reticulum (ER) dysfunction and subsequent cell death. Given evidence that the ER-embedded glucose-6-phosphate transporter (G6PT) regulates glioblastoma cell survival and that MT1-MMP is a key enzyme in the cancer cell invasive phenotype, we explored the molecular link between G6PT and MT1-MMP. Cytoskeleton-disrupting agents such as concanavalin A (ConA) and cytochalasin D triggered proMMP-2 activation and cell death in U87 glioma cells. ConA decreased G6PT gene expression, an event that was also observed in cells overexpressing the full-length recombinant MT1-MMP protein. Overexpression of a membrane-bound catalytically active but cytoplasmic domain-deleted MT1-MMP was unable to downregulate G6PT gene expression or to trigger necrosis. Gene silencing of MT1-MMP with small interfering RNA prevented proMMP-2 activation and induced G6PT gene expression. ConA inhibited Akt phosphorylation, whereas overexpression of recombinant G6PT rescued the cells from ConA-induced proMMP-2 activation and increased Akt phosphorylation. Altogether, new functions of MT1-MMP in cell death signaling may be linked to those of G6PT. Our study indicates a molecular signaling axis regulating the invasive phenotype of brain tumor cells and highlights a new "bioswitch" function for G6PT in cell survival.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiporters / physiology*
  • Brain Neoplasms / enzymology*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology*
  • Cell Death / genetics
  • Cell Line, Tumor
  • Enzyme Activation / genetics
  • Enzyme Precursors / genetics
  • Enzyme Precursors / metabolism*
  • Gelatinases / genetics
  • Gelatinases / metabolism*
  • Glioblastoma / enzymology*
  • Glioblastoma / genetics
  • Glioblastoma / pathology*
  • Humans
  • Matrix Metalloproteinase 14 / genetics
  • Matrix Metalloproteinase 14 / physiology*
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • Monosaccharide Transport Proteins / physiology*
  • Necrosis
  • Neoplasm Proteins / physiology
  • Phenotype
  • Signal Transduction* / genetics


  • Antiporters
  • Enzyme Precursors
  • Monosaccharide Transport Proteins
  • Neoplasm Proteins
  • SLC37A4 protein, human
  • Gelatinases
  • Metalloendopeptidases
  • progelatinase
  • Matrix Metalloproteinase 14