The Transient Receptor Potential Melastatin 7 Channel Regulates Pancreatic Cancer Cell Invasion through the Hsp90α/uPA/MMP2 pathway.
Fiche publication
Date publication
avril 2017
Journal
Neoplasia (New York, N.Y.)
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BRASSART Bertrand
Tous les auteurs :
Rybarczyk P, Vanlaeys A, Brassart B, Dhennin-Duthille I, Chatelain D, Sevestre H, Ouadid-Ahidouch H, Gautier M
Lien Pubmed
Résumé
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a very poor prognosis. There is an urgent need to better understand the molecular mechanisms that regulate PDAC cell aggressiveness. The transient receptor potential melastatin 7 (TRPM7) is a nonselective cationic channel that mainly conducts Ca and Mg. TRPM7 is overexpressed in numerous malignancies including PDAC. In the present study, we used the PANC-1 and MIA PaCa-2 cell lines to specifically assess the role of TRPM7 in cell invasion and matrix metalloproteinase secretion. We show that TRPM7 regulates Mg homeostasis and constitutive cation entry in both PDAC cell lines. Moreover, cell invasion is strongly reduced by TRPM7 silencing without affecting the cell viability. Conditioned media were further studied, by gel zymography, to detect matrix metalloproteinase (MMP) secretion in PDAC cells. Our results show that MMP-2, urokinase plasminogen activator (uPA), and heat-shock protein 90α (Hsp90α) secretions are significantly decreased in TRPM7-deficient PDAC cells. Moreover, TRPM7 expression in human PDAC lymph node metastasis is correlated to the channel expression in primary tumor. Taken together, our results show that TRPM7 is involved in PDAC cell invasion through regulation of Hsp90α/uPA/MMP-2 proteolytic axis, confirming that this channel could be a promising biomarker and possibly a target for PDAC metastasis therapy.
Mots clés
Calcium, metabolism, Cell Line, Tumor, Gene Expression, Gene Silencing, HSP90 Heat-Shock Proteins, metabolism, Humans, Lymphatic Metastasis, Magnesium, metabolism, Matrix Metalloproteinase 2, metabolism, Models, Biological, Pancreatic Neoplasms, genetics, Protein Binding, Protein-Serine-Threonine Kinases, genetics, Proteolysis, Signal Transduction, TRPM Cation Channels, genetics, Urokinase-Type Plasminogen Activator, metabolism
Référence
Neoplasia. 2017 04;19(4):288-300