New insights into the physiological role of carbonic anhydrase IX in tumour pH regulation

Abstract

In this review, we discuss the role of the tumour-associated carbonic anhydrase isoform IX (CAIX) in the context of pH regulation. We summarise recent experimental findings on the effect of CAIX on cell growth and survival, and present a diffusion-reaction model to help in the assessment of CAIX function under physiological conditions. CAIX emerges as an important facilitator of acid diffusion and acid transport, helping to overcome large cell-to-capillary distances that are characteristic of solid tumours. The source of substrate for CAIX catalysis is likely to be CO 2 , generated by adequately oxygenated mitochondria or from the titration of metabolic acids with HCO À 3 taken up from the extracellular milieu. The relative importance of these pathways will depend on oxygen and metabolite availability, the spatiotemporal patterns of the cell's exposure to hypoxia and on the regulation of metabolism by genes. This is now an important avenue for further investigation. The importance of CAIX in regulating tumour pH highlights the protein as a potential target for cancer therapy.

Benzenesulfonamides with benzimidazole moieties as inhibitors of carbonic anhydrases I, II, VII, XII and XIII

“…The enhanced activity of CAs is often related to various diseases. The isoforms CA IX and CA XII were intensively investigated enzymes during the last decade due to their overexpression in various human cancers [5][6][7][8][9] . Much work has been done to design selective CA IX and CA XII inhibitors.…”

Targeting Tumor Microenvironments for Cancer Prevention and Therapy

“…Carbonic anhydrase (CA) enzymes catalyze the reversible reaction between carbon dioxide and bicarbonate: CO 2 + H 2 O ↔ HCO 3 -+ H + , and facilitate the transport of CO 2 and H + ions for pH regulation (Swietach et al, 2010). There are 15 CA isoforms, I to XV, in mammalian cells, located in the cytosol, mitochondrion, extracellular plasma membrane, or secreted.…”

“…There are 15 CA isoforms, I to XV, in mammalian cells, located in the cytosol, mitochondrion, extracellular plasma membrane, or secreted. In particular, the isoform IX (CAIX) has been extensively studied in cancer biology (Swietach et al, 2010). The expression of CAIX is strongly induced by hypoxia and regulated by HIF-1.…”

“…To avoid the harmful accumulation of protons and decrease of intracellular pH (pHi), cancer cells must use the cellular transporter system to expel excess acids from the cells. Carbonic anhydrases (CA), monocarboxylate transporters (MCT), vacuolar-type H + -ATPase proton pump (V-ATPase), and sodium/hydrogen exchangers (NHE) play important roles in cellular pH regulation (Izumi et al, 2003;Swietach et al, 2010;Webb et al, 2011). Furthermore, recent studies have shown that a family of protonsensing G protein-coupled receptors regulates the behavior of tumor cells, immune cells, and blood vessels (Ludwig et al, 2003;Mogi et al, 2009;Yang et al, 2007).…”

Metabolic response of lung cancer cells to radiation in a paper-based 3D cell culture system

“…of !Our irradiation data for the multi-layer stacks showed that the sensitivity of cells to ionizing radiation decreased with increasing distance from the source of the oxygenated medium. To verify the cells were experiencing different oxygen tensions, we measured the expression of two markers for hypoxia in each of the six layers of the multilayer 3D culture: (i) hydroxy-HIF-1α, the predominant form of HIF-1α in cells when oxygenated (upon de-stacking) [68], and (ii) carbonic anhydrase 9 (CAIX), a HIF-1 inducible protein [69][70][71]. We stacked six sheets of lens paper-PVC composite containing overnight cultures of A549 (seeded at 2,000 A549 cells/zone) in an acrylic holder, cultured the stack for 4 days, disassembled the stacks into separate layers, and analyzed lysates for expression of hydroxy-HIF-1α and CAIX.…”