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Metabolites 2018, 8(1), 20; https://doi.org/10.3390/metabo8010020

Coordinated Regulation of Metabolic Transporters and Migration/Invasion by Carbonic Anhydrase IX

1
Department of Integrative Oncology, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada
2
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
*
Author to whom correspondence should be addressed.
Received: 16 February 2018 / Revised: 6 March 2018 / Accepted: 6 March 2018 / Published: 8 March 2018
(This article belongs to the Special Issue Carbonic Anhydrases and Metabolism)
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Abstract

Hypoxia is a prominent feature of the tumor microenvironment (TME) and cancer cells must dynamically adapt their metabolism to survive in these conditions. A major consequence of metabolic rewiring by cancer cells in hypoxia is the accumulation of acidic metabolites, leading to the perturbation of intracellular pH (pHi) homeostasis and increased acidosis in the TME. To mitigate the potentially detrimental consequences of an increasingly hypoxic and acidic TME, cancer cells employ a network of enzymes and transporters to regulate pH, particularly the extracellular facing carbonic anhydrase IX (CAIX) and CAXII. In addition to the role that these CAs play in the regulation of pH, recent proteome-wide analyses have revealed the presence of a complex CAIX interactome in cancer cells with roles in metabolite transport, tumor cell migration and invasion. Here, we explore the potential contributions of these interactions to the metabolic landscape of tumor cells in hypoxia and discuss the role of CAIX as a hub for the coordinated regulation of metabolic, migratory and invasive processes by cancer cells. We also discuss recent work targeting CAIX activity using highly selective small molecule inhibitors and briefly discuss ongoing clinical trials involving SLC-0111, a lead candidate small molecule inhibitor of CAIX/CAXII. View Full-Text
Keywords: hypoxia; carbonic anhydrase IX; cancer metabolism; transporter; integrin; MMP14; migration; invasion; metastasis hypoxia; carbonic anhydrase IX; cancer metabolism; transporter; integrin; MMP14; migration; invasion; metastasis
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McDonald, P.C.; Swayampakula, M.; Dedhar, S. Coordinated Regulation of Metabolic Transporters and Migration/Invasion by Carbonic Anhydrase IX. Metabolites 2018, 8, 20.

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