title: HRG-1 enhances cancer cell invasive potential and couples glucose metabolism to cytosolic/extracellular pH gradient regulation by the vacuolar-H(+) ATPase.
abstract: Haeme-responsive gene (HRG)-1 encodes a 16-kDa transmembrane protein that is induced by insulin-like growth factor-1 (IGF-1) and associates with the vacuolar-(H(+)) ATPase (V-ATPase). We previously reported that HRG-1 is essential for V-ATPase activity in endosomal acidification and receptor trafficking. Here, we show that in highly invasive and migratory cancer cell lines, HRG-1 and the V-ATPase are co-expressed at the plasma membrane, whereas in less invasive cell lines and non-transformed cells HRG-1 over-expression remains confined to intracellular compartments. Stable suppression of HRG-1 in invasive breast cancer MDA-MB-231 cells decreases extracellular pH, cell growth, migration and invasion. Ectopic expression of HRG-1 in non-invasive MCF-7 cells enhances V-ATPase activity, lowers the extracellular pH and increases the pH-dependent activity of MMP2 and MMP9 matrix metalloproteinases. HRG-1 enhances trafficking of the glucose transporter-1 (GLUT-1) with a concomitant increase in glucose uptake and lactate production. HRG-1 also promotes trafficking of the insulin-like growth factor I receptor (IGF-1R), β1-integrin and IGF-1 signalling. Taken together, our findings indicate that HRG-1 expression at the plasma membrane enhances V-ATPase activity, drives glycolytic flux and facilitates cancer cell growth, migration and invasion. Thus, HRG-1 may represent a novel target for selectively disrupting V-ATPase activity and the metastatic potential of cancer cells.
authors.affiliation: Cell Biology Laboratory, University College Cork, BioSciences Institute, College Road, Cork, Ireland.
authors.forename: F M
authors.initials: FM
authors.lastname: Fogarty
authors.affiliation: Cell Biology Laboratory, University College Cork, BioSciences Institute, College Road, Cork, Ireland.
authors.forename: J
authors.initials: J
authors.lastname: O'Keeffe
authors.affiliation: Laboratory of Biophysics and Bioanalysis, Department of Biochemistry, University College Cork, BioSciences Institute, College Road, Cork, Ireland.
authors.forename: A
authors.initials: A
authors.lastname: Zhadanov
authors.affiliation: Laboratory of Biophysics and Bioanalysis, Department of Biochemistry, University College Cork, BioSciences Institute, College Road, Cork, Ireland.
authors.forename: D
authors.initials: D
authors.lastname: Papkovsky
authors.affiliation: Cell Biology Laboratory, University College Cork, BioSciences Institute, College Road, Cork, Ireland.
authors.forename: V
authors.initials: V
authors.lastname: Ayllon
authors.affiliation: Cell Biology Laboratory, University College Cork, BioSciences Institute, College Road, Cork, Ireland.
authors.forename: R
authors.initials: R
authors.lastname: O'Connor
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D045604:Extracellular Fluid / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006420:Hemeproteins / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000378:metabolism; D061986:MCF-7 Cells; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D021381:Protein Transport; D025262:Vacuolar Proton-Translocating ATPases / Q000502:physiology*
chemical_list: D051272:Glucose Transporter Type 1; D006420:Hemeproteins; C495677:SLC2A1 protein, human; C546602:SLC48A1 protein, human; D019344:Lactic Acid; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D025262:Vacuolar Proton-Translocating ATPases; D005947:Glucose