Médecine moléculaire et génétique

Multifaceted Roles of Carbon Anhydrase IX in Cancer Cell Proliferation, Survival, Metastasis and Therapy Resistance and Indication of Promising Novel Therapies by its Inhibitors

Abstract

Mitsuru Sakitani

Cancer cells of solid tumors suffer from decrease in blood supply and hypoxia. To compensate deterioration in the intra-tumorous environment, hypoxia inducible factors, HIF-1α, HIF-2α and HIF-3α, are induced and numerous target genes are activated by these HIFs. Of these, CA9 is highly important because of its involvement in oncogenesis of solid tumors and malignant lymphomas. The essential function of CA9 in cancer is regulation of intracellular phi and extracellular pHe by mitigating the decreased pH due to excessed glycolysis in cancer cell. In this review article, first, CA9’s multifaceted roles in cancer cell proliferation, survival and metastasis and therapy resistance were summarized in association with effects of CA9 inhibitors. Second, after clarifying the CA9 activation via HIF-1α in the KRAS/RAF/MEK/ERK and PI3E/AKT/mTOR signaling pathways, molecular targeted therapies by means of CA9 inhibitors against therapy resistant triple negative breast cancer (TNBC), pancreatic ductal adenocarcinoma (PDAC), intraductal papillary mucinous neoplasms of the pancreas (IPMN) and adult T-cell leukemia/lymphoma (ATL) were shown to be promising novel therapies.