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

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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 +/Ca 2+ 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.

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          A microenvironmental model of carcinogenesis.

          Robert Gatenby, Robert Gillies (2008)
          We propose that carcinogenesis requires tumour populations to surmount six distinct microenvironmental proliferation barriers that arise in the adaptive landscapes of normal and premalignant populations growing from epithelial surfaces. Somatic evolution of invasive cancer can then be viewed as a sequence of phenotypical adaptations to these barriers. The genotypical and phenotypical heterogeneity of cancer populations is explained by an equivalence principle in which multiple strategies can successfully adapt to the same barrier. This model provides a theoretical framework in which the diverse cancer genotypes and phenotypes can be understood according to their roles as adaptive strategies to overcome specific microenvironmental growth constraints.
          Article 0 comments Cited 227 times – based on 0 reviews     Review now
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            pH sensing and regulation in cancer

            Mehdi Damaghi, Jonathan W Wojtkowiak, Robert Gillies (2013)
            Cells maintain intracellular pH (pHi) within a narrow range (7.1–7.2) by controlling membrane proton pumps and transporters whose activity is set by intra-cytoplasmic pH sensors. These sensors have the ability to recognize and induce cellular responses to maintain the pHi, often at the expense of acidifying the extracellular pH. In turn, extracellular acidification impacts cells via specific acid-sensing ion channels (ASICs) and proton-sensing G-protein coupled receptors (GPCRs). In this review, we will discuss some of the major players in proton sensing at the plasma membrane and their downstream consequences in cancer cells and how these pH-mediated changes affect processes such as migration and metastasis. The complex mechanisms by which they transduce acid pH signals to the cytoplasm and nucleus are not well understood. However, there is evidence that expression of proton-sensing GPCRs such as GPR4, TDAG8, and OGR1 can regulate aspects of tumorigenesis and invasion, including cofilin and talin regulated actin (de-)polymerization. Major mechanisms for maintenance of pHi homeostasis include monocarboxylate, bicarbonate, and proton transporters. Notably, there is little evidence suggesting a link between their activities and those of the extracellular H+-sensors, suggesting a mechanistic disconnect between intra- and extracellular pH. Understanding the mechanisms of pH sensing and regulation may lead to novel and informed therapeutic strategies that can target acidosis, a common physical hallmark of solid tumors.
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              Recent Developments in Targeting Carbonic Anhydrase IX for Cancer Therapeutics

              Paul McDonald, Jean-Yves Winum, Claudiu Supuran … (2012)
              Carbonic anhydrase IX (CAIX) is a hypoxia-inducible enzyme that is overexpressed by cancer cells from many tumor types, and is a component of the pH regulatory system invoked by these cells to combat the deleterious effects of a high rate of glycolytic metabolism. CAIX functions to help produce and maintain an intracellular pH (pHi) favorable for tumor cell growth and survival, while at the same time participating in the generation of an increasingly acidic extracellular space, facilitating tumor cell invasiveness. Pharmacologic interference of CAIX catalytic activity using monoclonal antibodies or CAIX-specific small molecule inhibitors, consequently disrupting pH regulation by cancer cells, has been shown recently to impair primary tumor growth and metastasis. Many of these agents are in preclinical or clinical development and constitute a novel, targeted strategy for cancer therapy.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cancers (Basel)
                Journal ID (iso-abbrev): Cancers (Basel)
                Journal ID (publisher-id): cancers
                Title: Cancers
                Publisher: MDPI
                ISSN (Electronic): 2072-6694
                Publication date (Electronic): 09 August 2019
                Publication date Collection: August 2019
                Volume: 11
                Issue: 8
                Electronic Location Identifier: 1139
                Affiliations
                [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 notes
                [* ]Correspondence: olga.krizanova@ 123456savba.sk ; Tel.: +4212-32295312
                Author information
                https://orcid.org/0000-0001-8329-3563
                Article
                Publisher ID: cancers-11-01139
                DOI: 10.3390/cancers11081139
                PMC ID: 6721473
                PubMed ID: 31395807
                SO-VID: 16d2b4a8-2337-4496-801f-b9a91bb0d483
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 16 July 2019
                Date accepted : 07 August 2019
                Categories
                Subject: Article

                Keywords: sodium calcium exchanger type 1,sodium proton exchanger type 1,carbonic anhydrase ix,hypoxic tumors,intracellular ph
                Data availability:
                Keywords: sodium calcium exchanger type 1, sodium proton exchanger type 1, carbonic anhydrase ix, hypoxic tumors, intracellular ph

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