Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH.

By J. Chiche, K. Ilc, Julie Laferrière, E. Trottier, Frédéric Dayan, N. Mazure, M. Brahimi-Horn, J. Pouysségur. Cancer Research, 2009

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Acidosis of the tumor microenvironment is typical of a malignant phenotype, particularly in hypoxic tumors. All cells express multiple isoforms of carbonic anhydrase (CA), enzymes catalyzing the reversible hydration of carbon dioxide into bicarbonate and protons. Tumor cells express membrane-bound CAIX and CAXII that are controlled via the hypoxia-inducible factor (HIF). Despite the recognition that tumor expression of HIF-1alpha and CAIX correlates with poor patient survival, the role of CAIX and CAXII in tumor growth is not fully resolved. To understand the advantage that tumor cells derive from expression of both CAIX and CAXII, we set up experiments to either force or invalidate the expression of these enzymes. In hypoxic LS174Tr tumor cells expressing either one or both CA isoforms, we show that (a) in response to a "CO(2) load," both CAs contribute to extracellular acidification and (b) both contribute to maintain a more alkaline resting intracellular pH (pH(i)), an action that preserves ATP levels and cell survival in a range of acidic outside pH (6.0-6.8) and low bicarbonate medium. In vivo experiments show that ca9 silencing alone leads to a 40% reduction in xenograft tumor volume with up-regulation of ca12 mRNA levels, whereas invalidation of both CAIX and CAXII gives an impressive 85% reduction. Thus, hypoxia-induced CAIX and CAXII are major tumor prosurvival pH(i)-regulating enzymes, and their combined targeting shows that they hold potential as anticancer targets.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/80a78847d283d35785a6f4b4f49d5346d47c2792

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Citations in the corpus

Targeting hypoxia in cancer therapy (2011, background): “The expression of CA9 and CA12 is controlled by HIF1 (Ref”
Defining the Role of Hypoxia-Inducible Factor 1 in Cancer Biology and Therapeutics (2009, neutral): “…immortalization, immune evasion (Lukashev et al., 2007), invasion and metastasis (Chan and Giaccia, 2007; Sullivan and Graham, 2007), proliferation, metabolism and pH regulation (Swietach et al., 2007; Chiche et al., 2009; Semenza, 2009b), and stem cell maintenance (Barnhart and Simon, 2007).”
Interfering with pH regulation in tumours as a therapeutic strategy (2011, background): “An interesting study reported that in hypoxic LS174Tr tumour cells that overexpress both CA9 and CA12, it was possible to genetically silence one or both carbonic anhydrase isoform”
Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer (2009, background): “Through this simple reaction CAIX and CAXII regulate tumour pH in contributing to acidification of the tumour environment [125, 126] and alkalinization of the cytoplasm [24, 127].”
Acidic extracellular microenvironment and cancer (2013, background): “Among them, CA IX in particular has been well studied in association with hypoxia and tumor survival through regulating intracellular pH [53,57].”
Acidity generated by the tumor microenvironment drives local invasion (2013, background): “These adaptations can involve, inter alia, upregulation of the sodium-hydrogen exchange (NHE-1) or carbonic anhydrase (CA-IX) (21-23) .”
Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. (2011, background): “Inhibition of CAIX inhibits metastasis of 4T1 breast tumors Although a reduction in colon tumor growth in response to CAIX depletion has been shown previously (22) and CAIX has been shown to influence cell migration in vitro”
Targeting metabolic transformation for cancer therapy (2010, background): “One strategy for directly targeting the acidification of the tumour is to inhibit members of the carbonic anhydrase (CA) family, and specifically the hypoxia-associated protein, CAIX”