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.

Vacuolar ATPase as a potential therapeutic target and mediator of treatment resistance in cancer

“…This is termed the Warburg effect and is associated with tumor hypoxia as well as activation of oncogenes, such as MYC and RAS, and inactivation of tumor suppressors, such as p53 65, 66, 67. This results in production of lactic acid and H + , and plasma membrane V‐ATPase may be key under these conditions for maintaining intracellular pH homeostasis 68. In addition, via its action as a coordinator of regulators of opposing anabolic versus catabolic pathways (eg, mediated via mTORC1 or AMPK, respectively) 10.…”

Saccharomyces cerevisiae Vacuolar H + -ATPase Regulation by Disassembly and Reassembly: One Structure and Multiple Signals

“…Moreover, V-ATPase mutations that impair binding to phosphofructokinase-1 are associated with distal renal tubular acidosis (24), and V-ATPase regulation by glycolysis plays a role in viral infections (40) and the metabolic switch in cancers (41,42). It has been proposed that glycolytic enzymes form a supercomplex with V-ATPase that funnels ATP directly to VATPase and propels proton transport (21,24,32,34,37,43).…”

TM9SF4 is a novel V-ATPase-interacting protein that modulates tumor pH alterations associated with drug resistance and invasiveness of colon cancer cells

“…[10][11][12][13] Recently, it has been shown that the expression of this proton pump is upregulated in several cancers, including colon cancer, even though its role in the latter remains poorly characterized. [14][15][16][17] TM9SF4 is a transmembrane protein belonging to the transmembrane-9 superfamily (TM9SF), which is a well-defined family of proteins characterized by a large hydrophilic N-terminal domain followed by nine transmembrane domains. 18 Although little is known about their function, these proteins have been implicated in adhesion, phagocytosis and innate immunity.…”