Carbonic anhydrase IX, a hypoxia-induced catalytic component of the pH regulating machinery in tumors

Abstract

Acidic tissue microenvironment contributes to tumor progression via multiple effects including the activation of angiogenic factors and proteases, reduced cell-cell adhesion, increased migration and invasion, etc. In addition, intratumoral acidosis can influence the uptake of anticancer drugs and modulate the response of tumors to conventional therapy. Acidification of the tumor microenvironment often develops due to hypoxia-triggered oncogenic metabolism, which leads to the extensive production of lactate, protons, and carbon dioxide. In order to avoid intracellular accumulation of the acidic metabolic products, which is incompatible with the survival and proliferation, tumor cells activate molecular machinery that regulates pH by driving transmembrane inside-out and outside-in ion fluxes. Carbonic anhydrase IX (CA IX) is a hypoxia-induced catalytic component of the bicarbonate import arm of this machinery. Through its catalytic activity, CA IX directly participates in many acidosis-induced features of tumor phenotype as demonstrated by manipulating its expression and/or by in vitro mutagenesis. CA IX can function as a survival factor protecting tumor cells from hypoxia and acidosis, as a pro-migratory factor facilitating cell movement and invasion, as a signaling molecule transducing extracellular signals to intracellular pathways (including major signaling and metabolic cascades) and converting intracellular signals to extracellular effects on adhesion, proteolysis, and other processes. These functional implications of CA IX in cancer are supported by numerous clinical studies demonstrating the association of CA IX with various clinical correlates and markers of aggressive tumor behavior. Although our understanding of the many faces of CA IX is still incomplete, existing knowledge supports the view that CA IX is a biologically and clinically relevant molecule, exploitable in anticancer strategies aimed at targeting adaptive responses to hypoxia and/or acidosis.

The Carbonic Anhydrase Inhibitor Ethoxzolamide Inhibits the Mycobacterium tuberculosis PhoPR Regulon and Esx-1 Secretion and Attenuates Virulence

“…ETZ would inhibit this process by inhibiting CA and limiting the accumulation of protons in the pseudoperiplasm. This model is inspired by models from Sedlakova et al (54) and Rasko and Sperandio (8).…”

High Monocarboxylate Transporter 4 Protein Expression in Stromal Cells Predicts Adverse Survival in Gastric Cancer

“…In addition, increasing evidences support that hypoxia-regulated gene expression accelerates tumor aggressive, contributing to the poorer outcome of patients with hypoxic tumors (Gee et al, 2010;Sergeant et al, 2011). CA IX is a pH regulating enzyme that regulates intracellular homeostasis and an indicator of hypoxia status.…”

“…Therefore, investigating the alteration of MCT4 expression in stroma cells may be a key point of understanding parenchyma-stroma metabolic coupling model and the aggressive microenvironment that benefits tumor progression. Carbonic anhydrase IX (CA IX) is a direct participator that is involved in cellular pH regulation processes through catalyzing the conversion of carbon dioxide to bicarbonate ions and protons (Sedlakova et al, 2014). In tumor cells, a couple of studies demonstrated that CA IX promotes tumor growth, invasion and metastasis, thus accelerating tumor development (Robertson et al, 2004;Chiche et al, 2009;Lou et al, 2011).…”

Cancer stem cells, their origin and niche: A search for the therapeutic target

“…Recent reports showed the role of TAFs in drug resistance, which is classified into two different types, that is soluble factor-mediated drug resistance (SFM-DR) and cell-adhesion-mediated drug resistance (CAM-DR) [89,90]. TAFs induces EMT by secreting carbonic anhydrase IX (CA IX) which causes acidification of ECM and further enhances the activities of MMP-2 and MMP-9 [91]. TAFs mediated overexpression of BCL-xL(B-cell lymphoma -extra-large) protect cancer cells from cytotoxic effects of tyrosine kinase inhibitors [92].…”