Intracellular pH Regulates Cancer and Stem Cell Behaviors: A Protein Dynamics Perspective

Abstract

The International Society of Cancer Metabolism (ISCaM) meeting on Cancer Metabolic Rewiring, held in Braga Portugal in October 2019, provided an outstanding forum for investigators to present current findings and views, and discuss ideas and future directions on fundamental biology as well as clinical translations. The first session on Cancer pH Dynamics was preceded by the opening keynote presentation from our group entitled Intracellular pH Regulation of Protein Dynamics: From Cancer to Stem Cell Behaviors. In this review we introduce a brief background on intracellular pH (pHi) dynamics, including how it is regulated as well as functional consequences, summarize key findings included in our presentation, and conclude with perspectives on how understanding the role of pHi dynamics in stem cells can be relevant for understanding how pHi dynamics enables cancer progression.

The Role of pHi in Intestinal Epithelial Proliferation–Transport Mechanisms, Regulatory Pathways, and Consequences

“…Recent progress in the drug development for CFTR corrector and modifiers with the potential to rescue CFTR function in CF patients may correct the pH i -regulatory dysfunction and reduce cancer risk (Phuan et al, 2019;Egan, 2020). The potential to combine direct pH i assessment with genetic, molecular biological and pharmacological tools, as already established for tumor cells (Liu et al, 2020;Stock, 2020), in intestinal organoids may provide insight into protonation/deprotonation events of key regulatory proteins in enterocyte proliferation and differentiation.…”

“…For decades, the role of steady-state pH i alterations has been addressed primarily in tumor cells. In cancer cells numerous H + extrusion and base loading mechanisms are upregulated, which generally leads to an inverted transmembrane pH gradient, characterized by alkalization of intracellular pH and extracellular acidosis, which is considered a hallmark of cancer metabolism (Webb et al, 2011;Swietach et al, 2014;Pedersen et al, 2017;Flinck et al, 2018;Becker and Deitmer, 2020;Liu et al, 2020). In this scenario, both the high intracellular and the low extracellular pH contribute to the malignant behavior (Pillai et al, 2019;Boedtkjer and Pedersen, 2020).…”

“…The interplay between apical or basolateral EGFR activation, different NHEs, and the pH i is not completely understood. It seems plausible that a constant slightly acidic pH i in the ISC zone may prevent hyperactivation of the signaling pathways that could result in hyperproliferation and possible tumor formation (Liu et al, 2020).…”

VISTA: A Mediator of Quiescence and a Promising Target in Cancer Immunotherapy

“…An acidic microenvironment created by lactic acid secretion can result in dysfunctional T cells by reduced expression of nuclear factor of activated T cells (NFAT) which results in less IFN-γ production [ 58 , 59 ]. The combination of low pHe and high intracellular pH (pHi) in tumors is achieved by elevated transmembrane acid extrusion [ 60 ]. The direct regulators of pH in the TME can be divided into regulators of cellular metabolism, that generate intracellular acidic products such as lactate and H + , and the transporters that move lactate and H + into the extracellular space ( Figure 4 ) [ 26 ].…”

“…Na + /H + exchangers release H + into the TME through the influx of Na + [ 26 ]. Cancer cells express vacuolar-ATPase (V-ATPase) on the cell surface through utilization of the a3 isoform, and this mediates the transport of cathepsins and H + from lysosomes to the TME [ 60 ]. In cancer cells, inhibition of cellular respiration by pyruvate dehydrogenase kinase (PDK) and increased activity of glucose transporter 1 (GLUT1), that transports glucose into the cell, promote glycolysis (the Warburg effect) [ 79 ].…”