title: A role for MT1-MMP as a cell death sensor/effector through the regulation of endoplasmic reticulum stress in U87 glioblastoma cells.
abstract: Recent findings in cell death signalling show that membrane type 1 matrix metalloproteinase (MT1-MMP), an MMP known for its involvement in cancer cell invasion and metastasis, can act as a "bioswitch" in the invasion versus cell death decision in brain tumour cells. Given that the endoplasmic reticulum (ER) is a subcellular compartment involved in metabolic control and cell death signalling and that cytoskeleton disruption, as encountered during cancer cell invasion, can lead to ER stress, we questioned whether MT1-MMP contributes to ER stress. We found that MT1-MMP gene silencing or pharmacological inhibition of vesicular trafficking with Brefeldin-A abrogated MT1-MMP cell surface-mediated proMMP-2 activation by the lectin Concanavalin-A (ConA) in U87 glioblastoma cells. ConA, also known to trigger the expression of pro-inflammatory cyclooxygenase (COX)-2 through MT1-MMP signalling from the plasma membrane, failed to do so when MT1-MMP was prevented from reaching the cell surface by Brefeldin-A. Gene silencing of MT1-MMP antagonized the expression of ConA-induced COX-2 and of the ER stress marker glucose-related protein 78 (GRP78), further suggesting that plasma membrane localization of MT1-MMP contributes to signalling ER stress. MT1-MMP maturation, which partially occurs during its trafficking from the ER to the plasma membrane, showed correlation of the 60 kDa MT1-MMP with GRP78 expression. Finally, Brefeldin-A treatment of glioblastoma cells led to Akt dephosphorylation; this effect was reversed when MT1-MMP was silenced. Collectively, our results provide a molecular rationale for a new role for MT1-MMP in the regulation of cancer cell death processes through ER stress signalling.
authors.affiliation: Laboratoire d'Oncologie Moléculaire, Département de Chimie, Centre de Recherche BioMED, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montreal, QC, H3C 3P8, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Proulx-Bonneau
authors.forename: Jonathan
authors.initials: J
authors.lastname: Pratt
authors.forename: Borhane
authors.initials: B
authors.lastname: Annabi
mesh_terms: D020126:Brefeldin A / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003208:Concanavalin A / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004347:Drug Interactions; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D005909:Glioblastoma / Q000473:pathology / Q000648:ultrastructure; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D034622:RNA Interference / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D014162:Transfection / Q000379:methods
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D011500:Protein Synthesis Inhibitors; D003208:Concanavalin A; D020126:Brefeldin A; D051546:Cyclooxygenase 2; D053511:Matrix Metalloproteinase 14