1. Carbonic anhydrase 9 confers resistance to ferroptosis/apoptosis in malignant mesothelioma under hypoxia
- Author
-
Tasuku Hirayama, Zan Li, Shinya Toyokuni, Li Jiang, Yoshitaka Sekido, and Shan Hwu Chew
- Subjects
Mesothelioma ,0301 basic medicine ,Programmed cell death ,Lung Neoplasms ,Clinical Biochemistry ,Apoptosis ,Mitochondrion ,Catalytic Fe(II) ,medicine.disease_cause ,Models, Biological ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Antigens, Neoplasm ,Cell Line, Tumor ,Carbonic anhydrase ,medicine ,Ferroptosis ,Humans ,Carbonic Anhydrase IX ,Hypoxia ,lcsh:QH301-705.5 ,Malignant mesothelioma ,Tumor biology ,lcsh:R5-920 ,biology ,Chemistry ,Mesothelioma, Malignant ,Organic Chemistry ,Carbonic Anhydrase 9 ,Iron metabolism ,Mitochondria ,030104 developmental biology ,lcsh:Biology (General) ,Cancer cell ,biology.protein ,Cancer research ,Mitochondrial fission ,Reactive Oxygen Species ,Carcinogenesis ,lcsh:Medicine (General) ,Biomarkers ,030217 neurology & neurosurgery ,Research Paper - Abstract
Hypoxia and acidity provide microenvironment for selection under evolutionary pressure and proliferation in cancer cells. Carbonic anhydrases (CAs) are a superfamily of metalloenzymes present in all life kingdoms, equilibrating the reactions among CO2, bicarbonate and H+. CA9, a membrane-associated α-CA, has been a drug target for various cancers. Whereas iron is essential not only for cancer cells but also for all the lives on earth, little is known on the association among hypoxia, iron metabolism, extracellular acidity and redox regulation. Malignant mesothelioma (MM), an aggressive tumor with poor prognosis, is an intriguing model in that asbestos-associated pathogenesis includes excess iron environment during carcinogenesis. Re-analysis of rat asbestos-induced MM model revealed an inverse association between high CA9 expression and survival. Here we used human MMs to identify the molecular events surrounding CA9 from the viewpoint of iron metabolism. CA9 expression was significantly higher in MM cells than in MeT-5A mesothelial cells, which was further amplified under hypoxia (1%O2) with increased catalytic Fe(II). CA9 suppression by inhibitors (S4 and U104) decreased viability and migration of MM cells, accompanied by overexpression of TFRC, IREB1/2 and FPN1(SLC40A1) and by downregulation of FTH/FTL. This expressional pattern was similar to that of erastin-induced ferroptosis in the same cells. Furthermore, we observed mitochondrial fission and enhanced autophagy with increased catalytic Fe(II) in both mitochondria and lysosomes after CA9 inhibition, accompanied by increased peroxides, mitochondrial O2− and lipid peroxidation. The eventual cell death was significantly inhibited by deferoxamine, ferrostatin-1 and Z-VAD-FMK, suggesting a mixed cell death of ferroptosis and apoptosis. Therefore, CA9 plays a role in equilibrating among hypoxia, iron metabolism and redox regulation in MM cells., Graphical abstract Image 1
- Published
- 2019