"Na+-H+ Exchanger, pH Regulation and Cancer." - GreenMedInfo Summary
Na+-H+ Exchanger, pH Regulation and Cancer.
Recent Pat Anticancer Drug Discov. 2012 Jun 25. Epub 2012 Jun 25. PMID: 22738122
Department of Bioscience, Biotechnology and Pharmacological Science, University of Bari, 70126 Bari, Italy. firstname.lastname@example.org.
Cancer cells and tissues, regardless of their origin and genetic background, have an aberrant regulation of hydrogen ion dynamics leading to a reversal of the intracellular to extracellular pH gradient (∆pHi to ∆pHe) in cancer cells and tissue as compared to normal tissue. This perturbation in pH dynamics rises very early in carcinogenesis and is one of the most common patho-physiological hallmarks of tumors. Recently, there has been a very large increase in our knowledge of the importance androles of pHi and pHe in developing and driving a series of tumor hallmarks. This reversed proton gradient is driven by a series of proton export mechanisms that underlie the initiation and progression of the neoplastic process. In this context, one of the primary and best studied regulators of bothpHi and pHe in tumors is the Na+/H+ exchanger isoform 1 (NHE1). The NHE1 is an integral membrane transport protein involved in regulating pH and in tumor cells is a major contributor to the production and maintainance of their reversed proton gradient. It is activated during oncogene-dependent transformation resulting in cytosolic alkalinization which the drives subsequent hallmark behaviors including growth factor- and substrate-independent growth, and glycolytic metabolism. It is further activated by various growth factors, hormone, the metabolic microenvironment (low serum, acidic pHe and hypoxia) or by ECM receptor activation. This review will present the recent progress in understanding the role the NHE1 in determining tumor progression and invadopodia-guided invasion/metastasis and recent patents for NHE1 inhibitors and novel therapeutic protocols for anti-NHE1 pharmacological approaches. These may represent a real possibility to open up new avenues for wide-spread and efficient treatments against cancer.