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Review
. 2013 Dec 17:4:370.
doi: 10.3389/fphys.2013.00370.

pH sensing and regulation in cancer

Mehdi Damaghi  1 , Jonathan W Wojtkowiak  1 , Robert J Gillies  1
Affiliations
Review

pH sensing and regulation in cancer

Mehdi Damaghi et al. Front Physiol. .

Abstract

Cells maintain intracellular pH (pHi) within a narrow range (7.1-7.2) by controlling membrane proton pumps and transporters whose activity is set by intra-cytoplasmic pH sensors. These sensors have the ability to recognize and induce cellular responses to maintain the pHi, often at the expense of acidifying the extracellular pH. In turn, extracellular acidification impacts cells via specific acid-sensing ion channels (ASICs) and proton-sensing G-protein coupled receptors (GPCRs). In this review, we will discuss some of the major players in proton sensing at the plasma membrane and their downstream consequences in cancer cells and how these pH-mediated changes affect processes such as migration and metastasis. The complex mechanisms by which they transduce acid pH signals to the cytoplasm and nucleus are not well understood. However, there is evidence that expression of proton-sensing GPCRs such as GPR4, TDAG8, and OGR1 can regulate aspects of tumorigenesis and invasion, including cofilin and talin regulated actin (de-)polymerization. Major mechanisms for maintenance of pHi homeostasis include monocarboxylate, bicarbonate, and proton transporters. Notably, there is little evidence suggesting a link between their activities and those of the extracellular H(+)-sensors, suggesting a mechanistic disconnect between intra- and extracellular pH. Understanding the mechanisms of pH sensing and regulation may lead to novel and informed therapeutic strategies that can target acidosis, a common physical hallmark of solid tumors.

Keywords: buffer therapy; cancer microenvironment; extracellular acidification; intracellular pH; pH regulators; proton sensors.

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Figures

Figure 1
Figure 1
Reversed extracellular and intracellular pH in cancer cells compared to normal cells. Cancer cells have a reversed pH gradient compared with normal differentiated cells that is cancer cells have a higher pHi and a lower pHe than normal cells in acute acidosis conditions. The pHe becomes even lower (~6.7) in chronic acidosis. This disruption facilitates the adaptive behaviors of cancer cells such as cytoskeleton remodeling and directed migration, apoptosis evasion, extracellular matrix (ECM) remodeling, invasion, and metastasis.
Figure 2
Figure 2
Major pH regulators in a cancer cell. After glucose uptake by specific transporters (GLUT1 and GLUT3), glucose is converted to pyruvate, generating 2 ATP per glucose and proton. Based on Pasteur effect, in the presence of oxygen, pyruvate is oxidized to HCO−3, generating 36 additional ATP per glucose; in the absence of oxygen pyruvate is reduced to lactate, which is exported to extracellular space. However, as Warburg proposed glycolysis is potent in cancer cells. Notably both processes produce protons (H+), which cause acidification of the extracellular space. This figure represents main proteins that regulate intracellular and extracellular pH in tumors, including: monocarboxylate transporters (MCTs), which transport lactic acid and other monocarboxylates formed by the glycolytic degradation of glucose; the plasma membrane proton pump vacuolar ATPase (V-ATPase); Na+/H+ exchangers (NHEs); anion exchangers (AEs); carbonic anhydrases (CAII, CAIX, and CA XII); Na+/HCO−3 co-transporters (NBCs), and HCO−3-transporters (BTs).
Figure 3
Figure 3
Cancer cells express proton-sensing GPCRs such as GPR4, TDAG8, and OGR1 to regulate their tumorigenesis and invasion. TDAG8 and OGR1 sense extracellular protons, leading to activation of the cAMP signaling pathway. OGR1 is usually coupled with the PLC/Ca2+ pathway through Gq/11 proteins and GPR4 and TDAG8 are coupled with the adenylyl cyclase/cAMP pathway through Gs proteins in the cells to PKA and ERK signaling pathway that play pivotal roles in cancer progression.
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