Abstract
Alterations in tumour metabolism and acid/base regulation result in the formation of a hostile environment, which fosters tumour growth and metastasis. Acid/base homoeostasis in cancer cells is governed by the concerted interplay between carbonic anhydrases (CAs) and various transport proteins, which either mediate proton extrusion or the shuttling of acid/base equivalents, such as bicarbonate and lactate, across the cell membrane. Accumulating evidence suggests that some of these transporters interact both directly and functionally with CAIX to form a protein complex coined the ‘transport metabolon’. Transport metabolons formed between bicarbonate transporters and CAIX require CA catalytic activity and have a function in cancer cell migration and invasion. Another type of transport metabolon is formed by CAIX and monocarboxylate transporters. In this complex, CAIX functions as a proton antenna for the transporter, which drives the export of lactate and protons from the cell. Since CAIX is almost exclusively expressed in cancer cells, these transport metabolons might serve as promising targets to interfere with tumour pH regulation and energy metabolism. This review provides an overview of the current state of research on the function of CAIX in tumour acid/base transport and discusses how CAIX transport metabolons could be exploited in modern cancer therapy.
Highlights
Anti-CD147 displaces CAIX from the transporter–chaperone complex, thereby acting as a ‘metabolon disruptor',189 while anti-PG was suggested to interfere with the shuttling function of CAIX.[114]. These findings provide a proof of concept that the MCT1/ 4–CD147–CAIX transport metabolon is a potential target that could be exploited to interfere with cancer cell metabolism to reduce cell proliferation and thereby inhibit tumour progression
Tumour pH regulation is governed by the concerted interplay between various acid/base transporters and carbonic anhydrases (CAs), some of which form a structural and functional complex, coined the ‘transport metabolon’
CAIX can directly interact with the HCO3− transporters NBCe1 and AE2 in the leading edge of migrating cancer cells to facilitate HCO3− flux across the plasma membrane and support the generation of a pH gradient at the cell’s protruding front, which drives cancer cell migration and thereby formation of metastasis.[72]
Summary
Alterations in tumour metabolism and acid/base regulation result in the formation of a hostile environment, which fosters tumour growth and metastasis. Transport metabolons formed between bicarbonate transporters and CAIX require CA catalytic activity and have a function in cancer cell migration and invasion. Another type of transport metabolon is formed by CAIX and monocarboxylate transporters. Since CAIX is almost exclusively expressed in cancer cells, these transport metabolons might serve as promising targets to interfere with tumour pH regulation and energy metabolism. This review provides an overview of the current state of research on the function of CAIX in tumour acid/base transport and discusses how CAIX transport metabolons could be exploited in modern cancer therapy.
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