Proton channels and exchangers in cancer

Abstract

Although cancer is characterized by an intratumoral genetic heterogeneity, a totally deranged pH control is a common feature of most cancer histotypes. Major determinants of aberrant pH gradient in cancer are proton exchangers and transporters, including V-ATPase, Na+/H+ exchanger (NHE), monocarboxylate transporters (MCTs) and carbonic anhydrases (CAs). Thanks to the activity of these proton transporters and exchangers, cancer becomes isolated and/or protected not only from the body reaction against the growing tumor, but also from the vast majority of drugs that when protonated into the acidic tumor microenvironment do not enter into cancer cells. Proton transporters and exchangers represent a key feature tumor cells use to survive in the very hostile microenvironmental conditions that they create and maintain. Detoxifying mechanisms may thus represent both a key survival option and a selection outcome for cells that behave as unicellular microorganisms rather than belonging to an organ, compartment or body. It is, in fact, typical of malignant tumors that, after a clinically measurable yet transient initial response to a therapy, resistant tumor clones emerge and proliferate, thus bursting a more malignant behavior and rapid tumor progression. This review critically presents the background of a novel and efficient approach that aims to fight cancer through blocking or inhibiting well characterized proton exchangers and transporters active in human cancer cells. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.

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

“…The first three classes of transporters are involved in H + extrusion (64), but all have been implicated in cancer progression (65). These H + transporters interact with NHE1 in cancer cells and contribute to H + signalling; however, we present evidence that, in triple-negative breast cancer, particularly of the basal-like clinical subtype, it is the manipulation of NHE1 activity that shows the most promise in terms of therapeutic gain.…”

“…pH homeostasis in normal and tumour cells is regulated by a variety of plasma membrane-bound transporters and pumps including the: Na + /H + exchangers, sodium bicarbonate co-transporters, anion exchangers, monocarboxylate transporters, carbonic anhydrases, and vacuolar proton pump ATPases (V-ATPases) [Reviewed in (33,64)]. While combinatorial approaches targeting more than one transporter may be an option, to the best of our knowledge, there is currently no evidence to suggest pharmacological inhibition of multiple transporters would have an additive anti-cancer effect and this could be an area for further study.…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…As op posed to nor mal tis sue, tu mors are in deed char ac ter ized by a more acidic ex tra cel lu lar pH (pHe) and a slightly al ka line in tra cel lu lar pH (pHi) [147][148][149]. This re sults from the ab nor mal meta bolic ac tiv ity of can cer cells, in clud ing in creased gly colytic flux and lac tic acid re lease [150]; car bon diox ide pro duc tion by the TCA cy cle and the pen tose phos phate path way (PPP) [151][152][153][154]; over ex pres sion or up reg u lated ac tiv ity of car bonic an hy drases [155,156] and pro ton trans porters [156]; and de creased pro ton clear ance in the tu mor en vi ron ment [157]. Pro ton ex tru sion and ex tra cel lu lar acid i fi ca tion make ad her ent junc tions lose [158], stim u late mi gra tion and cy toskele ton re or ga ni za tion [159][160][161][162][163], and pro mote the ex pres sion [164,165], re lease [166,167] and ac tiv ity [167,168] of pro teases that de grade the ex tra cel lu lar ma trix.…”

A nonmainstream approach against cancer

“…Hyperfunction of proton pumps is a hallmark of very cancer cells 9,11 . However, many other ''proton or ion exchangers'' are involved in cancer cell homeostasis, and inhibition of these molecules always leads to potent anti-tumor effects 13 . In fact, tumor cells are obliged to survive in a very hostile microenvironment characterized by low nutrient supply, hypoxia and low pH 14 .…”

“…In fact, tumor cells are obliged to survive in a very hostile microenvironment characterized by low nutrient supply, hypoxia and low pH 14 . Proton pumps help the cancer cells to eliminate quickly H+, to avoid intracellular acidification 13 . The way cancer cells get to the generation of this acidic microenvironment, so hostile to normal cells that are not equipped to survive in the same conditions 15 , is not entirely built.…”