The Na+-H+ Exchanger (NHE1) in pH Regulation and Cancer
Pp. 384-417 (34)
Stephan J. Reshkin, Rosa A. Cardone, Katrine Zeeberg, Maria R. Greco and Salvador Harguindey
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 (ΔpHi to ΔpHe) as compared to normal tissues.
This perturbation in pH dynamics occurs very early in carcinogenesis and is one of the
most common pathophysiological hallmarks of tumors. Recently, there has been quite a
significant increase in our knowledge of the importance and roles 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 both pHi 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
maintenance of their reversed proton gradient. It is activated during oncogene-dependent
transformation resulting in cytosolic alkalinization which drives subsequent hallmark
behaviors including growth factor- and substrate-independent growth, and glycolytic
metabolism. It is further activated by various growth factors, hormones, the metabolic
microenvironment (low serum, acidic pHe and hypoxia) or by ECM receptor activation.
This chapter will present the recent progress in understanding the role of 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.
Amiloride, angiogenesis, cariporide, growth factors, HOE642,
invadopodia, invasion, MDR, metastasis, Na+/H+ exchanger, NHE1, pH and cancer,
pH therapy, proton transport in cancer, tumor metabolism, tumor microenvironment.
Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy.