Abstract
Intra- and extracellular pH regulation is a pivotal function of all cells and tissues. Net outward transport of H+ is a prerequisite for normal physiological function, since a number of intracellular processes, such as metabolism and energy supply, produce acid. In tumor tissues, distorted pH regulation results in extracellular acidification and the formation of a hostile environment in which cancer cells can outcompete healthy local host cells. Cancer cells employ a variety of H+/HCO3−-coupled transporters in combination with intra- and extracellular carbonic anhydrase (CA) isoforms, to alter intra- and extracellular pH to values that promote tumor progression. Many of the transporters could closely associate to CAs, to form a protein complex coined “transport metabolon”. While transport metabolons built with HCO3−-coupled transporters require CA catalytic activity, transport metabolons with monocarboxylate transporters (MCTs) operate independently from CA catalytic function. In this article, we assess some of the processes and functions of CAs for tumor pH regulation and discuss the role of intra- and extracellular pH regulation for cancer pathogenesis and therapeutic intervention.
Highlights
Regulation of intracellular and extracellular tumor pH is governed by the concerted interplay between cytosolic and exofacial carbonic anhydrases and acid/base transporters, the expression and activity of which are often modified during tumorigenesis
AE2 was shown to accumulate at the leading edge of migrating cancer cells, where it colocalizes with NBCe1 and NHE1 [85,86]
The antibody displaces CAIX from the monocarboxylate transporters (MCTs)-CD147 complex and leads to disruption of the transport metabolon [117]. These experiments provide a proof of concept that targeting of the MCT-CD147-CAIX transport metabolon, either by interference with the CAIX antenna function or by disruption of the protein complex, can provide a useful tool for future tumor therapy
Summary
Out of the 15 human CA isoforms, CAIX and CAXII have received most attention in cancer tissue, both as diagnostic markers and potential drug targets. AE2 was shown to accumulate at the leading edge of migrating cancer cells, where it colocalizes with NBCe1 and NHE1 [85,86] In this compartment, AE2 exports HCO3 − (which was imported by the NBC) in exchange for osmotically active Cl− to support local water uptake via aquaporins [86]. The colocalization between the bicarbonate transporters and CAIX was most evident in the leading edge of migrating cells [86,98] In line with these findings, it was shown that expression of catalytic active CAIX facilitates cell migration in MDCK and hypoxic HeLa cells [86], while inhibition of CAIX catalytic activity results in impaired formation of invadopodia and degradation of the extracellular matrix [98]. An in-depth discussion on the various types of acid/base transport metabolons, including the controversy about this concept, is given by a number of reviews [91,97,111,112,113,114]
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