Amith, SR and Fong, S and Baksh, S and Fliegel, L (2015) Na (+)/H (+)exchange in the tumour microenvironment: does NHE1 drive breast cancer carcinogenesis? International Journal of Developmental Biology, 59 (7-9). 367 -377. ISSN 1696-3547

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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 C-terminal 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.

Item Type: Article
Additional Information: This is the final published version of the article (version of record). It first appeared online via University of the Basque Country Press at http://dx.doi.org/10.1387/ijdb.140336lf - please refer to any applicable terms of use of the publisher.
Uncontrolled Keywords: NHE1, breast cancer, metastasis, carcinogenesis, chemotherapy
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
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Depositing User: Symplectic
Date Deposited: 19 Jan 2017 09:54
Last Modified: 19 Jan 2017 10:03
URI: http://eprints.keele.ac.uk/id/eprint/2794

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