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

Abstract

Cytoskeleton disorganization is an early step in the activation process of matrix metalloproteinase 2 (MMP-2) by membrane type 1 MMP (MTi-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 MT1MMP is a key enzyme in the cancer cell invasive phenotype, we explored the molecular link between G6PT and MTi-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 fulllength recombinant MTi-MMP protein. Overexpression of a membrane-bound catalytically active but cytoplasmic domain-deleted MTi-MMP was unable to downregulate G6PT gene expression or to trigger necrosis. Gene silencing of MTi-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 MTi-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.

Keywords

• Glioma
• cytoskeleton
• glucose-6-phosphate transporter
• MT1MMP
• necrosis