A role for MT1-MMP as a cell death sensor/effector through the regulation of endoplasmic reticulum stress in U87 glioblastoma cells
- 375 Downloads
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.
KeywordsEndoplasmic reticulum stress MT1-MMP Concanavalin-A
Glucose-related protein 78
Membrane type 1 matrix metalloproteinase
BA holds a Canada Research Chair in Molecular Oncology from the Canadian Institutes of Health Research (CIHR). SPB is a Fonds Québécois de la Recherche sur la Nature et les Technologies (FQRNT) awardee. JP is a Natural Sciences and Engineering Research Council of Canada (NSERC) awardee. This study was funded by a grant from the NSERC to BA.
- 22.Fortier S, Touaibia M, Lord-Dufour S, Galipeau J, Roy R, Annabi B (2008) Tetra- and hexavalent mannosides inhibit the pro-apoptotic, antiproliferative and cell surface clustering effects of concanavalin-A: impact on MT1-MMP functions in marrow-derived mesenchymal stromal cells. Glycobiology 18:195–204PubMedCrossRefGoogle Scholar
- 24.Yu M, Bowden ET, Sitlani J, Sato H, Seiki M, Mueller SC, Thompson EW (1997) Tyrosine phosphorylation mediates ConA-induced membrane type 1-matrix metalloproteinase expression and matrix metalloproteinase-2 activation in MDA-MB-231 human breast carcinoma cells. Cancer Res 57:5028–5032PubMedGoogle Scholar
- 31.Meriane M, Duhamel S, Lejeune L, Galipeau J, Annabi B (2006) Cooperation of matrix metalloproteinases with the RhoA/Rho kinase and mitogen-activated protein kinase kinase-1/extracellular signal-regulated kinase signalling pathways is required for the sphingosine-1-phosphate-induced mobilization of marrow-derived stromal cells. Stem Cells 24:2557–2565PubMedCrossRefGoogle Scholar
- 35.Markovic DS, Vinnakota K, Chirasani S, Synowitz M, Raguet H, Stock K, Sliwa M, Lehmann S, Kälin R, van Rooijen N, Holmbeck K, Heppner FL, Kiwit J, Matyash V, Lehnardt S, Kaminska B, Glass R, Kettenmann H (2009) Gliomas induce and exploit microglial MT1-MMP expression for tumour expansion. Proc Natl Acad Sci USA 106:12530–12535PubMedCrossRefGoogle Scholar
- 36.Golubkov VS, Cieplak P, Chekanov AV, Ratnikov BI, Aleshin AE, Golubkova NV, Postnova TI, Radichev IA, Rozanov DV, Zhu W, Motamedchaboki K, Strongin AY (2010) Internal cleavages of the autoinhibitory prodomain are required for membrane type-1 matrix metalloproteinase activation while furin cleavage alone generates inactive proteinase. J Biol Chem 285:27726–27736PubMedCrossRefGoogle Scholar
- 46.Kuipers GK, Slotman BJ, Wedekind LE, Stoter TR, Berg J, Sminia P, Lafleur MV (2007) Radiosensitization of human glioma cells by cyclooxygenase-2 (COX-2) inhibition: independent on COX-2 expression and dependent on the COX-2 inhibitor and sequence of administration. Int J Radiat Biol 83:677–685PubMedCrossRefGoogle Scholar
- 48.Kardosh A, Golden EB, Pyrko P, Uddin J, Hofman FM, Chen TC, Louie SG, Petasis NA, Schönthal AH (2008) Aggravated endoplasmic reticulum stress as a basis for enhanced glioblastoma cell killing by bortezomib in combination with celecoxib or its non-coxib analogue, 2,5-dimethyl-celecoxib. Cancer Res 68:843–851PubMedCrossRefGoogle Scholar