The proteoglycan-like domain of carbonic anhydrase IX mediates non-catalytic facilitation of lactate transport in cancer cells

// Samantha Ames 1 , Silvia Pastorekova 2 and Holger M. Becker 1, 3 1 Division of General Zoology, Department of Biology, University of Kaiserslautern, Kaiserslautern, Germany 2 Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic 3 Institute of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany Correspondence to: Holger M. Becker, email: Holger.Becker@tiho-hannover.de Keywords: monocarboxylate transporter; proton antenna; hypoxia; breast cancer; Xenopus oocyte Received: November 29, 2017 Accepted: April 19, 2018 Published: June 15, 2018 ABSTRACT Highly glycolytic tumor cells release vast amounts of lactate and protons via monocarboxylate transporters (MCTs), which exacerbate extracellular acidification and support the formation of a hostile environment. Transport activity of MCTs can be facilitated by non-catalytic interaction with carbonic anhydrase IX (CAIX), the expression of which has been shown to be upregulated under hypoxia. We have now studied the mechanisms that enable CAIX-mediated facilitation of proton-coupled lactate transport in breast cancer cells and Xenopus oocytes. Our results indicate that the proteoglycan like (PG) domain of CAIX could function as ‘proton antenna’ to facilitate MCT transport activity. Truncation of the PG domain and application of a PG-binding antibody significantly reduced proton-coupled lactate transport in MCT-expressing oocytes and hypoxic breast cancer cells, respectively. Furthermore, application of the PG-binding antibody reduced proliferation and migration of hypoxic cancer cells, suggesting that facilitation of proton-coupled lactate flux by the CAIX PG domain contributes to cancer cell survival under hypoxic conditions.