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Carbonic anhydrase IX inhibition affects viability of cancer cells adapted to extracellular acidosis

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Abstract

Among the players of the adaptive response of cancer cells able to promote a resistant and aggressive phenotype, carbonic anhydrase IX (CAIX) recently has emerged as one of the most relevant drug targets. Indeed, CAIX targeting has received a lot of interest, and selective inhibitors are currently under clinical trials. Hypoxia has been identified as the master inductor of CAIX, but, to date, very few is known about the influence that another important characteristic of tumor microenvironment, i.e., extracellular acidosis, exerts on CAIX expression and activity. In the last decades, acidic microenvironment has been associated with aggressive tumor phenotype endowed with epithelial-to-mesenchymal transition (EMT) profile, high invasive and migratory ability, apoptosis, and drug resistance. We demonstrated that melanoma, breast, and colorectal cancer cells transiently and chronically exposed to acidified medium (pH 6.7 ± 0.1) showed a significantly increased CAIX expression compared to those grown in standard conditions (pH 7.4 ± 0.1). Moreover, we observed that the CAIX inhibitor FC16-670A (also named SLC-0111, which just successfully ended phase I clinical trials) not only prevents such increased expression under acidosis but also promotes apoptotic and necrotic programs only in acidified cancer cells. Thus, CAIX could represent a selective target of acidic cancer cells and FC16-670A inhibitor as a useful tool to affect this aggressive subpopulation characterized by conventional therapy escape.

Key messages

  • Cancer cells overexpress CAIX under transient and chronic extracellular acidosis.

  • Acidosis-induced CAIX overexpression is NF-κB mediated and HIF-1α independent.

  • FC16-670A prevents CAIX overexpression and induces acidified cancer cell death.

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Acknowledgements

This study was financially supported by grants from Istituto Toscano Tumori.

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Authors and Affiliations

  1. Department of Clinical and Experimental Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy

    Elena Andreucci, Silvia Peppicelli, Jessica Ruzzolini, Francesca Bianchini & Lido Calorini

  2. Istituto Toscano Tumori (ITT), Florence, Italy

    Elena Andreucci, Silvia Peppicelli, Francesca Bianchini & Lido Calorini

  3. Department of NEUROFARBA, University of Florence, Florence, Italy

    Fabrizio Carta & Claudiu T. Supuran

  4. DISCOG, University of Padova, Padova, Italy

    Giulia Brisotto

  5. Immunology and Molecular Oncology Unit, IOV-IRCCS, Padova, Italy

    Giulia Brisotto

  6. Immunopathology and Cancer Biomarkers, Traslational Research Department, IRCCS, C.R.O. National Cancer Institute, Aviano, Pordenone, Italy

    Giulia Brisotto & Eva Biscontin

  7. Department of Surgery and Translational Medicine, University of Florence, Florence, Italy

    Alessio Biagioni

  8. Excellence Centre for Research, Transfer and High Education DENOTHE, Florence, Italy

    Lido Calorini

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  1. Elena Andreucci
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  2. Silvia Peppicelli
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  10. Lido Calorini
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Correspondence to Lido Calorini.

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Andreucci, E., Peppicelli, S., Carta, F. et al. Carbonic anhydrase IX inhibition affects viability of cancer cells adapted to extracellular acidosis. J Mol Med 95, 1341–1353 (2017). https://doi.org/10.1007/s00109-017-1590-9

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  • DOI: https://doi.org/10.1007/s00109-017-1590-9

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