Advances in research on the regulatory mechanism of NHE1 in tumors (Review)

Abstract

Tumors pose a major threat to human health and present with difficulties that modern medicine has yet to overcome. It has been demonstrated that the acid-base balance of the tumor microenvironment is closely associated with the dynamic balance in the human body and that it regulates several processes, such as cell proliferation and differentiation, intracellular enzyme activity, and cytoskeletal assembly and depolymerization. It has been well established that the regulation of intra-and extracellular pH depends on a series of functional ion transporters and hydrogen ion channels, such as the Na + /H + exchanger (NHE) protein and thee Cl/HCO 3-exchange protein, among which the NHE1 member of the NHE family has been attracting increasing attention in recent years, particularly in studies on the correlation between pH regulation and tumors. NHE1 is a housekeeping gene encoding a protein that is widely expressed on the surface of all plasma membranes. Due to its functional domain, which determines the pHi at its N-terminus and C-terminus, NHE1 is involved in the regulation of the cellular pH microenvironment. It has been reported in the literature that NHE1 can regulate cell volume, participate in the transmembrane transport of intracellular and extracellular ions, affect cell proliferation and apoptosis, and regulate cell behavior and cell cycle progression; however, research on the role of NHE1 in tumorigenesis and tumor development in various systems is at its early stages. The aim of the present study was to review the current research on the correlation between the NHE family proteins and various systemic tumors, in order to indicate a new direction for antitumor drug development with the pH microenvironment as the target.

Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression

“…Recruited by Src-dependent cortactin phosphorylation, NHE1 exchanges here locally extracellular Na + for intracellular H + . The resulting increase in intracellular pH leads, via clustering of phosphatidyl-inositol-4,5-bisphosphate, to an activation of cofilin, thus regulating the actin-dependent pushing force of the cell protrusion [ 403 , 404 ]. Src is required for the organization of the cytoskeleton in osteoclasts and is, therefore, indispensable for efficient bone resorption [ 405 ].…”

Tumor acidity: From hallmark of cancer to target of treatment

“…The cooperative use of MCT1/MCT4 inhibitors or nonspecific MCT inhibitors has good therapeutic potential ( 125 , 132 , 134 , 135 ). Also of great importance to decrease pHi values is the pharmacological inhibition of the proton pump H + -ATPase ( 136 ), sodium-hydrogen antiporter 1 (NHE1) ( 137 ), and carbonic anhydrase IX (CAIX) ( 138 ). For example, according to the results of a phase III clinical trial (NCT01069081), intermittent use of a high dose of the proton pump inhibitor esomeprazole potentiates the effects of docetaxel and cisplatin chemotherapy in metastatic breast cancer without causing further toxicity ( 139 ).…”

The Role of Plasma Membrane Sodium/Hydrogen Exchangers in Gastrointestinal Functions: Proliferation and Differentiation, Fluid/Electrolyte Transport and Barrier Integrity

“…Over the following decades, the mechanisms of an altered pH i climate in many cancers including esophageal, gastric and colonic cancer, the consequences for malignant proliferation, as well as the importance of the NHE1 isoform in the maintenance of malignant growth and the potential to influence malignant growth by manipulating NHE1 activity, was intensely studied, as well as reviewed ( Reshkin et al, 2000 ; Fang et al, 2008 ; Liu et al, 2008 ; Boedtkjer et al, 2012 ; Sharma et al, 2015 ; Parks et al, 2017 ; Stock and Pedersen, 2017 ; Cao et al, 2019 ; Cardone et al, 2019 ; Hu et al, 2021 ). Because of the existence of many excellent reviews, the present one will not include the role of NHE1 in gastrointestinal malignancies.…”