A non-catalytic function of carbonic anhydrase IX contributes to the glycolytic phenotype and pH regulation in human breast cancer cells

Abstract

The most aggressive and invasive tumor cells often reside in hypoxic microenvironments and rely heavily on rapid anaerobic glycolysis for energy production. This switch from oxidative phosphorylation to glycolysis, along with up-regulation of the glucose transport system, significantly increases the release of lactic acid from cells into the tumor microenvironment.Excess lactate and proton excretion exacerbate extracellular acidification to which cancer cells, but not normal cells, adapt. We have hypothesized that carbonic anhydrases (CAs) play a role in stabilizing both intracellular and extracellular pH to favor cancer progression and metastasis.Here we show that proton efflux (acidification) using the glycolytic rate assay is dependent on both extracellular pH (pH e ) and CA IX expression. Yet, isoform selective sulfonamide-based inhibitors of CA IX did not alter proton flux, which suggests that the catalytic activity of CA IX is not necessary for this regulation. Other investigators have suggested the CA IX cooperates with the MCT transport family to excrete protons. To test this possibility, we examined the expression patterns of selected ion transporters and show that members of this family are differentially expressed within the molecular subtypes of breast cancer. The most aggressive form of breast cancer, triple negative breast cancer (TNBC), appears to coordinately express the monocarboxylate transporter 4 (MCT4) and carbonic anhydrase IX (CA IX). This supports a possible mechanism that utilizes the intramolecular H + shuttle system in CA IX to facilitate proton efflux through MCT4.

CAIX forms a transport metabolon with monocarboxylate transporters in human breast cancer cells

“…Inhibition of CAIX catalytic activity has been widely considered as a potential therapeutic strategy for hypoxic tumors [75]. However, most of the inhibitors tested so far bind to a moiety apart from the His200 and might therefore not target the direct and functional interaction between MCT1/4-CD147 and CAIX [76]. To test whether disruption of the MCT-CD147-CAIX transport metabolon could impact on cancer cell metabolism and decrease cell proliferation we used an antibody against CD147 (Anti-CD147), which targets a moiety close to the CD147-Glu73.…”

Warburg effect in colorectal cancer: the emerging roles in tumor microenvironment and therapeutic implications

“…Tumor cells rely on MCTs as well as CAs to export redundant protons and lactate and maintain the acidbase balance [302]. In addition, CAIX has been reported to significantly promote the lactate flux of MCT1 and glycolytic rates in a non-catalytic manner [303,304]. Indisulam/E7070 is an efficient inhibitor against multiple CAs [305] and could not only suppress the proliferation of CRC cell lines but also lead to a decrease in the tumor volume of xenograft CRC models, highlighting the powerful anti-tumor ability [306].…”

GHB Toxicokinetics and Renal Monocarboxylate Transporter Expression are Influenced by the Estrus Cycle in Rats

“…Intracellular carbonic anhydrase II was demonstrated to increase MCT1 activity without a corresponding increase in MCT1 membrane expression. Extracellular carbonic anhydrases IV and IX were demonstrated to augment the activity of MCT1 (39)(40)(41)(42). Additionally, expression of carbonic anhydrase-related proteins VIII, X and XI in Xenopus oocytes were demonstrated to increase the activity of co-expressed MCT1 (43).…”