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CAIX forms a transport metabolon with monocarboxylate transporters in human breast cancer cells

Oncogene volume 39, pages 1710–1723 (2020)Cite this article

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Abstract

Tumor cells rely on glycolysis to meet their elevated demand for energy. Thereby they produce significant amounts of lactate and protons, which are exported via monocarboxylate transporters (MCTs), supporting the formation of an acidic microenvironment. The present study demonstrates that carbonic anhydrase IX (CAIX), one of the major acid/base regulators in cancer cells, forms a protein complex with MCT1 and MCT4 in tissue samples from human breast cancer patients, but not healthy breast tissue. Formation of this transport metabolon requires binding of CAIX to the Ig1 domain of the MCT1/4 chaperon CD147 and is required for CAIX-mediated facilitation of MCT1/4 activity. Application of an antibody, directed against the CD147-Ig1 domain, displaces CAIX from the transporter and suppresses CAIX-mediated facilitation of proton-coupled lactate transport. In cancer cells, this “metabolon disruption” results in a decrease in lactate transport, reduced glycolysis, and ultimately reduced cell proliferation. Taken together, the study shows that carbonic anhydrases form transport metabolons with acid/base transporters in human tumor tissue and that these interactions can be exploited to interfere with tumor metabolism and proliferation.

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Acknowledgements

We thank Heike Kanapin, Sandra Pfeiffer, Hans-Peter Schneider, and Patrick Pattar for technical assistance. The work was funded by the Deutsche Forschungsgemeinschaft (to H.M.B.; BE 4310/6–1), the Research Initiative BioComp (to H.M.B), and by stipends from the Lotto-Stiftung Rheinland-Pfalz and the FAZIT Stiftung (to S.A.).

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  1. Division of General Zoology, Department of Biology, University of Kaiserslautern (TUK), D-67653, Kaiserslautern, Germany

    Samantha Ames & Holger M. Becker

  2. Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, 32610, USA

    Jacob T. Andring & Robert McKenna

  3. Institute of Physiological Chemistry, University of Veterinary Medicine Hannover, D-30559, Hannover, Germany

    Holger M. Becker

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Ames, S., Andring, J.T., McKenna, R. et al. CAIX forms a transport metabolon with monocarboxylate transporters in human breast cancer cells. Oncogene 39, 1710–1723 (2020). https://doi.org/10.1038/s41388-019-1098-6

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