Hypoxia-induced CA IX cooperates with elements of glycolytic metabolism in tumor cells

Authors: Radivojka Vulić 1    Martin Benej 1    Eliška Švastová 1    Marko Repič 1    Monica Vitale 2,3    Nicola Zambrano 2,3    Andrea Scaloni 4    Juraj Kopáček 1    Silvia Pastoreková 1   
1 Institute of Virology, BMC SAS, Dúbravská cesta 9, 845 05 Batislava, Slovakia    2 Dipartimento di Biochimica e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80131 Napoli, Italy    3 CEINGE Biotecnologie Avanzate, 80145 Napoli, Italy    4 Proteomics and Mass Spectrometry Laboratory, ISPAAM, National Research Council, 80147 Napoli, Italy   
Year: 2016
Section: Cellular metabolism, physiology, molecular biology and genetics
Abstract No.: 1468
ISBN: 978-80-972360-0-7

Insufficient oxygen supply, hypoxia, is one of the most typical phenomena characterizing a tumor microenvironment. A typical manifestation of adaptation to hypoxia is a metabolic shift from mitochondrial respiration to glycolysis and the formation of an acidic cell microenvironment [1]. Hypoxia and related acidosis disrupt normal physiologic functions and play a role in promoting the invasiveness, metastases, chemoresistance and immunoresistance in tumor cells [2, 3]. Adaptation to hypoxia and extracellular acidosis represent a crucial step for cell survival. The tumor cells express a wide range of genes whose products allow adaptation to these limiting factors [4]. One of them, carbonic anhydrase IX (CA IX) is a hypoxia-induced catalytically active enzyme which contributes to neutralization of the intracellular pH, and to acidification of the extracellular pH [5, 6]. In terms of contribution to the extracellular acidosis, CA IX is regarded as the active component of the prometastatic cascade, cell adhesion and cell migration [7]. The expression of CA IX is strongly associated with poor prognosis and the malignant phenotype. In this study, we present evidence of a novel relationship between CA IX and glycolysis and suggest that CA IX via its expression and catalytic activity cooperates with components of glycolytic metabolism. We believe that our results will contribute to a better understanding of the role of CA IX in cancer metabolism.

Financial support: Research and Development Support Agency (APVV-0658-11), 7th Framework program of EU (Collaborative project METOXIA), Slovak Scientific Grant Agency (VEGA 2/0130/11), Research and Development Operational Program funded by the ERDF (project ITMS 26240220062).
[1] Fang J. S., Gillies R. D., & Gatenby R. Adaptation to hypoxia and acidosis in carcinogenesis and tumor progression. Seminars in Cancer Biology 2008; 18(5): 330–7.
[2] Reshkin S. J., Cardone R. a & Harguindey S. Na+-H+ exchanger, pH regulation and cancer. Recent Patents on Anti-Cancer Drug Discovery 2013; 8(1): 85–99.
[3] Weljie A. M., & Jirik F. R. Hypoxia-induced metabolic shifts in cancer cells: moving beyond the Warburg effect. The International Journal of Biochemistry & Cell Biology 2011; 43(7): 981–9.
[4] Brahimi-Horn M. C., Bellot G., & Pouysségur, J. Hypoxia and energetic tumour metabolism. Current Opinion in Genetics & Development 2011; 21(1): 67–72.
[5] Pastorekova S, Zavadova Z, Kostal M, Babusikova O, Zavada J. A novel quasi-viral agent, MaTu, is a two-component system. Virology 1992; 187 (2):620-626.
[6] Svastova E, Hulikova A, Rafajova M, Zat'ovicova M, Gibadulinova A, et al. Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS letters 2004; 577 (3):439-445.
[7] Svastova E, Witarski W, Csaderova L, Kosik I, Skvarkova L, et al. Carbonic Anhydrase IX Interacts with Bicarbonate Transporters in Lamellipodia and Increases Cell Migration via Its Catalytic Domain. J Biol Chem 2012; 287 (5):3392-3402.