Na+/H+ exchange in the tumour microenvironment: does NHE1 drive breast cancer carcinogenesis?

Abstract

Ionic messengers signal several critical events in carcinogenesis, including metastasis, the leading cause of patient mortality. The aberrant metabolic, proliferative and anti-apoptotic nature of neoplastic cells can be traced to the abnormal expression of their ion transporters and related signalling networks. In this manuscript, we discuss Na + /H + flux, as mediated by the sodium-hydrogen exchanger isoform 1 (NHE1), a major ion transporter involved in tumourigenesis. Allosteric activation of NHE1 by external stimuli is controlled by phosphorylation of key amino acids on its cytosolic Cterminal tail, which also acts as a signal scaffold for its regulation by intracellular protein and lipid binding partners. In breast cancer cells, pH homeostasis and proton dynamics are disrupted early in transformation. This constitutively activates NHE1, causing a reversal of the plasma membrane pH gradient, resulting in a more alkaline intracellular pH and a more acidic extracellular pH. NHE1-mediated cellular alkalinization potentiates cytoskeletal remodelling, mobilizing cells for directed migration. Concomitant redistribution of NHE1 to invadopodia, where increased proton extrusion promotes proteolytic digestion of the extracellular matrix, primes cells for invasion into the bloodstream. NHE1 hyperactivity therefore heralds an important stage in cancer cell development, critically facilitating the acquisition of the invasive phenotype necessary for metastasis to occur. The potential for targeting NHE1 in the development of novel chemotherapeutic applications is explored.

KR-33028, a potent inhibitor of the Na+/H+ exchanger NHE1, suppresses metastatic potential of triple-negative breast cancer cells

“…The mechanism of the potentiation is not yet known but could be that NHE1 inhibition mediates prevention of proton extrusion which blocks NHE1 enhancement of mitosis, and this may accentuate paclitaxel anti-mitotic effects. Alternatively, inhibition of NHE1 may block reversal of the proton gradient, preventing extracellular acidification which could neutralize paclitaxel efficacy or uptake [5]. Interestingly, the co-adjuvant effect of EMD87580 or HMA with paclitaxel was not observed in hormone receptor-positive, luminal MCF-7 cells, or MDA-MB-231 cells lacking NHE1 expression [9].…”

“…NHE1 is an integral membrane protein 815 amino acids in length that is ubiquitously expressed in mammalian cells [3]. It comprises an N-terminal transmembrane domain through which ion exchange occurs, and a cytosolic C-terminal domain that regulates exchanger activity via phosphorylation by kinases and association with lipid and protein binding partners [4,5]. NHE1 plays a critical role in cancer cells, becoming hyperactive in cells undergoing neoplastic transformation.…”

“…5-(N, N-hexamethylene)-amiloride; HMA; 5 pyrazinoyl guanidines), and the highly selective acylguanidines (e.g. cariporide, benzoyl guanidine).…”

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

“…This is not due to changes in Na + kinetics or NHE1 expression, but is due to an alkaline shift in the pHi activation curve (72). In highly invasive triple-negative basal-like MDA-MB-231 breast cancer cells, there is a similar pattern of NHE1 activation by serum deprivation (53). NHE1 activation in low serum in MCF-7 and MDA-MB-231 cells is initiated through a sequential RhoA/p160ROCK/p38MAPK signal cascade gated by protein kinase A (PKA)-mediated phosphorylation of RhoA (73).…”

“…Several different serine/threonine kinases can activate NHE1 by phosphorylation, in addition to the exchanger's activation by its intracellular binding partners (extensively reviewed in (48,51,53). Examples of kinase-mediated activators of NHE1 include: extracellular signal regulated kinases ERK1/2 which are important in the activation of NHE1 in response to intracellular acidosis, and for which NHE1 serves as a signal scaffold (54,55); AKT (protein kinase B) which activates NHE1 in response to insulin and platelet-derived growth factor in fibroblasts (56), but inhibits NHE1 activity in cardiomyocytes (57); -Raf which phosphorylates NHE1 at amino acid threonine 653 (58); and p90 ribosomal S6 kinase (p90 RSK ) which phosphorylates NHE1 at serine 703, activating the exchanger in response to serum (59).…”