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Open AccessArticle

Type 1 Sodium Calcium Exchanger Forms a Complex with Carbonic Anhydrase IX and Via Reverse Mode Activity Contributes to pH Control in Hypoxic Tumors

1
Institute of Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Dúbravská cesta, 84505 Bratislava, Slovakia
2
Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dúbravská cesta, 84505 Bratislava, Slovakia
3
Department of Chemistry, Faculty of Natural Sciences, University of Ss. Cyril and Methodius, Námestie J. Herdu 2, 91701 Trnava, Slovakia
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(8), 1139; https://doi.org/10.3390/cancers11081139
Received: 16 July 2019 / Revised: 2 August 2019 / Accepted: 7 August 2019 / Published: 9 August 2019
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Abstract

Hypoxia and acidosis are among the key microenvironmental factors that contribute to cancer progression. We have explored a possibility that the type 1Na+/Ca2+ exchanger (NCX1) is involved in pH control in hypoxic tumors. We focused on changes in intracellular pH, co-localization of NCX1, carbonic anhydrase IX (CA IX), and sodium proton exchanger type 1 (NHE1) by proximity ligation assay, immunoprecipitation, spheroid formation assay and migration of cells due to treatment with KB-R7943, a selective inhibitor of the reverse-mode NCX1. In cancer cells exposed to hypoxia, reverse-mode NCX1 forms a membrane complex primarily with CA IX and also with NHE1. NCX1/CA IX/NHE1 assembly operates as a metabolon with a potent ability to extrude protons to the extracellular space and thereby facilitate acidosis. KB-R7943 prevents formation of this metabolon and reduces cell migration. Thus, we have shown that in hypoxic cancer cells, NCX1 operates in a reverse mode and participates in pH regulation in hypoxic tumors via cooperation with CAIX and NHE1. View Full-Text
Keywords: sodium calcium exchanger type 1; sodium proton exchanger type 1; carbonic anhydrase IX; hypoxic tumors; intracellular pH sodium calcium exchanger type 1; sodium proton exchanger type 1; carbonic anhydrase IX; hypoxic tumors; intracellular pH
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Liskova, V.; Hudecova, S.; Lencesova, L.; Iuliano, F.; Sirova, M.; Ondrias, K.; Pastorekova, S.; Krizanova, O. Type 1 Sodium Calcium Exchanger Forms a Complex with Carbonic Anhydrase IX and Via Reverse Mode Activity Contributes to pH Control in Hypoxic Tumors. Cancers 2019, 11, 1139.

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