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PMID: 17460777 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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 (New York, N.Y.) ·Vol. 9 ·No. 4 ·2007-04-00 ·Pages 332-40

Belkaid A, Fortier S, Cao J, Annabi B

Abstract

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.

MeSH Terms
Antiporters/physiology Brain Neoplasms/enzymology,genetics,pathology Cell Death/genetics Cell Line, Tumor Enzyme Activation/genetics Enzyme Precursors/genetics,metabolism Gelatinases/genetics,metabolism Glioblastoma/enzymology,genetics,pathology Humans Matrix Metalloproteinase 14/genetics,physiology Metalloendopeptidases/genetics,metabolism Monosaccharide Transport Proteins/physiology Necrosis Neoplasm Proteins/physiology Phenotype Signal Transduction/genetics
Chemicals
Antiporters Enzyme Precursors Monosaccharide Transport Proteins Neoplasm Proteins SLC37A4 protein, human Gelatinases Metalloendopeptidases progelatinase Matrix Metalloproteinase 14
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Belkaid Anissa
Laboratoire d'Oncologie Moléculaire, Département de Chimie, Centre BIOMED, Université du Québec à Montréal, Quebec, Canada.
Fortier Simon
Cao Jian
Annabi Borhane
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Article Info
Journal
Neoplasia (New York, N.Y.)
Abbr.
Neoplasia
ISSN
1476-5586
DOI
10.1593/neo.07142
Published
2007-04-00
Pages
332-40
Language
English
Region
United States
NLM ID
100886622
PMCID
PMC1854846
Subset
IM
Grants
NCI NIH HHS · R01 CA113553 · United States
NCI NIH HHS · 1R01CA113553-01A1 · United States
External Links
PubMed source DOI: 10.1593/neo.07142 PMC Full Text View journal details
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