Na + /H + antiporter (NHE1) and lactate/H + symporters (MCTs) in pH homeostasis and cancer metabolism

Abstract

The Na(+)/H(+)-exchanger NHE1 and the monocarboxylate transporters MCT1 and MCT4 are crucial for intracellular pH regulation, particularly under active metabolism. NHE1, a reversible antiporter, uses the energy provided by the Na(+) gradient to expel H(+) ions generated in the cytosol. The reversible H(+)/lactate(-) symporters MCT1 and 4 cotransport lactate and proton, leading to the net extrusion of lactic acid in glycolytic tumors. In the first two sections of this article we review important features and remaining questions on the structure, biochemical function and cellular roles of these transporters. We then use a fully-coupled mathematical model to simulate their relative contribution to pH regulation in response to lactate production, as it occurs in highly hypoxic and glycolytic tumor cells. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.

pH, Lactate, and Hypoxia: Reciprocity in Regulating High-Affinity Monocarboxylate Transporter Expression in Glioblastoma

“…Whereas the pH i of normal tissues is ~7.2 with pH e being ~7.4 (the physiological pH), malignant tumors harbor a pH i of ~7.4 with pH e of ~6.8 [70]. Acid–base regulation in tumor cells is facilitated by an assemblage of plasma-membrane transporters including MCTs, Na + /H + exchangers, HCO 3 − transporters and associated anion exchangers, vacuolar H + -ATPases, and carbonic anhydrases [71], [72]. Regulatory factors that recruit cytoplasmic signaling proteins to the membrane receptors to facilitate and promote glioma dissemination have also been reported [73].…”

Cancer cell behaviors mediated by dysregulated pH dynamics at a glance

“…The activity of these transporters is regulated not only by changes in pH i as a homeostatic mechanism but also by intra-or extra-cellular cues, such as oncogenes (GrilloHill et al, 2015;Reshkin et al, 2014), growth factor signaling (Counillon and Pouyssegur, 1995;Clement et al, 2013;Meima et al, 2009;Counillon et al, 2016), metabolic burden (Odunewu and Fliegel, 2013;Wu and Kraut, 2014), hypoxia and osmolarity (Lacroix et al, 2008;Counillon et al, 2016). In cancer cells, pH i is increased compared to normal cells (∼7.3-7.6 versus ∼7.2), while extracellular pH ( pH e ) is decreased (∼6.8-7.0 versus ∼7.4; see poster).…”

“…This reversed pH gradient in cancer cells is an early event in cancer development (Reshkin et al, 2000) and increases during neoplastic progression (Cardone et al, 2005). The higher pH i in cancer cells is paradoxical, considering that metabolic acids are generated through increased metabolism and proliferation; however, an increased pH i is maintained in cancer cells through the increased expression or activity of plasma membrane ion transporters and pH i regulators, including the Na + -H + exchanger 1 (NHE1) (Cong et al, 2014;Reshkin et al, 2014), carbonic anhydrases (CAs) (Zheng et al, 2015;Gallagher et al, 2015), monocarboxylate transporter 1 and 4 (MCT1 and MCT4, respectively) (Counillon et al, 2016), and Na + -driven HCO 3 − exchangers (Parks and Pouyssegur, 2015;Lee et al, 2016;Gorbatenko et al, 2014). The dysregulated pH of cancer cells enables cellular processes that are sensitive to small changes in pH i , including cell proliferation, migration and metabolism.…”

Genetic disruption of the pHi-regulating proteins Na+/H+ exchanger 1 (SLC9A1) and carbonic anhydrase 9 severely reduces growth of colon cancer cells

“…Unfortunately, toxicity due to NHE1 inhibitors in concomitant cardiac clinical trials resulted in their abandonment in all areas of the clinic (see [3, 13] for a more extensive discussion). Despite this, NHE1 continues to be investigated for its importance in tumor cell progression and in particular cell migration/metastasis and blockade of the H + secreting strategy in cancer cells remains an attractive therapeutic target [14–17]. …”