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.
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.
Belkaid
Anissa
A
Laboratoire d'Oncologie Moléculaire, Département de Chimie, Centre BIOMED, Université du Québec à Montréal, Quebec, Canada.
Fortier
Simon
S
Cao
Jian
J
Annabi
Borhane
B
D017920:Antiporters / Q000502:physiology*; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000235:genetics; D004792:Enzyme Precursors / Q000235:genetics / Q000378:metabolism*; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism*; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000502:physiology*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D009004:Monosaccharide Transport Proteins / Q000502:physiology*; D009336:Necrosis; D009363:Neoplasm Proteins / Q000502:physiology; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics
D017920:Antiporters; D004792:Enzyme Precursors; D009004:Monosaccharide Transport Proteins; D009363:Neoplasm Proteins; C503531:SLC37A4 protein, human; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase; D053511:Matrix Metalloproteinase 14