Carbonic Anhydrase IX: Regulation and Role in Cancer

Abstract

Tumor microenvironment substantially influences the process of tumorigenesis. In many solid tumors, imbalance between the demand of rapidly proliferating cancer cells and the capabilities of the vascular system generates areas with insufficient oxygen supply. In response to tumor hypoxia, cancer cells modulate their gene expression pattern to match the requirements of the altered microenvironment. One of the most significant adaptations to this milieu is the shift towards anaerobic glycolysis to keep up the energy demands. This oncogenic metabolism is often maintained also in aerobic cells. Lactic acid, its metabolic end-product, accumulates hand-in-hand with carbon dioxide, leading to acidification of the extracellular environment. Carbonic anhydrase IX (CA IX) is the most widely expressed gene in response to hypoxia. Its crucial role in intracellular pH maintenance represents the means by which cancer cells adapt to the toxic conditions of the extracellular milieu. Furthermore, the activity of CA IX stimulates the migratory pathways of cancer cells and is connected with the increase of the aggressive/invasive phenotype of tumors. CA IX expression in many types of tumors indicates its relevance as a general marker of tumor hypoxia. Moreover, its expression is closely related to prognosis of the clinical outcome in several tumor types. All above mentioned facts support the strong position of CA IX as a potential drug therapy target. Here, we summarize the state-of-the-art knowledge on its regulation and role in cancer development.

3′UTR polymorphisms of carbonic anhydrase IX determine the miR-34a targeting efficiency and prognosis of hepatocellular carcinoma

“…In addition to its crucial role in intracellular pH maintenance, the activity of CA9 also stimulates aggressive phenotypes of different cancer cells 18, 19 . However, the functional roles of CA9 in HCC cells remain largely unknown.…”

“…CA9 expression and activity in cancer cells are tightly regulated at multiple levels, including DNA methylation, transcription, post-translational modification, and proteinase-mediated cleavage 18, 47, 48 . Above all, CA9 is best known as a hypoxia-inducible factor (HIF)-1α target gene under hypoxic conditions.…”

Role of carbonic anhydrases in skin wound healing

“…CAs are enzymes that convert carbon dioxide and water to bicarbonate and protons. 3, 4, 5 Because the intracellular pH must remain stable, all excess acidity is efficiently exported from the cells, which in turn acidifies the extracellular environment to provide a favorable environment for cancer cell migration and invasion. 25 CAs have been linked to this process in reports showing a CA inhibitor-induced reduction of cancer cell invasion in contrast to a facilitation of cancer cell migration and invasion by CA expression.…”

“…3, 4 Carbonic anhydrases (CA) are a family of zinc metalloenzymes that regulate the tissue acid–base equilibrium by catalyzing the reversible hydration of carbon dioxide to bicarbonate ions and protons (CO 2 +H 2 O<–>HCO 3 − +H + ). 3, 4, 5 Fifteen human CA isoforms have been found, of which 12 are active and 3 inactive. 6, 7 These isoenzymes are expressed to some extent in all tissues and organs, but particularly in those that are metabolically highly active such as the brain and kidney.…”

“…6, 7 These isoenzymes are expressed to some extent in all tissues and organs, but particularly in those that are metabolically highly active such as the brain and kidney. 3, 5 Interestingly, the expression of CA proteins IX and XII is induced by hypoxia in different tumors. 8 Through their ability to regulate pH and generate an acidic environment, these enzymes endow tumor cells with survival advantages under hypoxia/acidosis conditions and confer an increased ability to migrate.…”