Expression Dynamics of CA IX Epitope in Cancer Cells under Intermittent Hypoxia Correlates with Extracellular pH Drop and Cell Killing by Ureido-Sulfonamide CA IX Inhibitors

Abstract

Carbonic anhydrase IX (CA IX) is a membrane-bound CA isozyme over-expressed in many hypoxic tumor cells, where it ensures pH homeostasis and has been implicated in tumor survival, metastasis and resistance to chemotherapy and radiotherapy. Given the functional importance of CA IX in tumor biochemistry, we investigated the expression dynamics of CA IX in normoxia, hypoxia and intermittent hypoxia, which are typical conditions experienced by tumor cells in aggressive carcinomas. We correlated the CA IX epitope expression dynamics with extracellular pH acidification and with viability of CA IX-expressing cancer cells upon treatment with CA IX inhibitors (CAIs) in colon HT-29, breast MDA-MB-231 and ovarian SKOV-3 tumor cell models. We observed that the CA IX epitope expressed under hypoxia by these cancer cells is retained in a significant amount upon reoxygenation, probably to preserve their proliferation ability. The extracellular pH drop correlated well with the level of CA IX expression, with the intermittent hypoxic cells showing a similar pH drop to fully hypoxic ones. All cancer cells showed higher sensitivity to CA IX inhibitors (CAIs) under hypoxia as compared to normoxia. The tumor cell sensitivity to CAIs under hypoxia and intermittent hypoxia were similar and higher than in normoxia and appeared to be correlated with the lipophilicity of the CAI.

Immunophenotypes and Tumor Immune Microenvironment in Hepatocellular Carcinoma With Macrotrabecular Massive and Vessels Encapsulating Tumor Clusters

“…In addition, the prevalence of CA IX expression was notably higher in HCC exhibiting the MTM pattern when compared to other subtypes, in line with findings from a prior study (24). CA IX is not specific to HCCs and its expression is observed in various carcinomas, inducing hypoxic conditions (25)(26)(27)(28). In pathological diagnosis, morphological and immunophenotypic findings as well as high levels of tumor markers can be useful.…”

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“…It is found that some antigens or receptors are over-expressed on the surface of tumour cells [107]. Normal cells normally express various receptors like folate, prostate-specific membrane antigen, biotin, transferrin, peptide and carbonic anhydrase IX [108]. Active targeting is based on the specific recognition between receptor and ligand or the covalent modification of targeting groups on the surface.…”

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“…Meanwhile, the overexpression of CA IX also provides a clear survival advantage for cancer cells and confers tumor resistance to conventional chemotherapy and immunotherapy. [46,47] In addition, activation of HIF-1 significantly increases CA IX expression in hypoxic environments. Several researches have proved that CA IX could be strongly upregulated by the over expression of HIF-1 and play a central role in hypoxia-mediated tumor heterogeneity.…”