Targeting carbonic anhydrase IX improves the anti-cancer efficacy of mTOR inhibitors
| Autor: | Seraina Faes, Tania Santoro, Dipak Datta, Nicolo Riggi, Jean-Christophe Stehle, Catherine Pythoud, Janine Horlbeck, Emilie Uldry, Anne Planche, Nicolas Demartines, Igor Letovanec, Olivier Dormond |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Mice Nude mTORC1 Small hairpin RNA 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Animals Humans Medicine Pimonidazole Carbonic Anhydrase IX Carbonic Anhydrase Inhibitors Hypoxia PI3K/AKT/mTOR pathway Sirolimus Antibiotics Antineoplastic Tumor hypoxia rapamycin business.industry TOR Serine-Threonine Kinases CAIX Drug Synergism Neoplasms Experimental Xenograft Model Antitumor Assays Acetazolamide Mice Inbred C57BL Treatment Outcome 030104 developmental biology Oncology 030220 oncology & carcinogenesis Immunology Cancer cell mTOR Cancer research Female RNA Interference Colorectal Neoplasms business HT29 Cells Research Paper Acetazolamide/pharmacology Antibiotics Antineoplastic/pharmacology Carbonic Anhydrase IX/antagonists & inhibitors Carbonic Anhydrase IX/genetics Carbonic Anhydrase IX/metabolism Carbonic Anhydrase Inhibitors/pharmacology Colorectal Neoplasms/drug therapy Colorectal Neoplasms/genetics Colorectal Neoplasms/metabolism Neoplasms Experimental/drug therapy Neoplasms Experimental/genetics Neoplasms Experimental/metabolism Sirolimus/pharmacology TOR Serine-Threonine Kinases/antagonists & inhibitors TOR Serine-Threonine Kinases/metabolism acetazolamide hypoxia medicine.drug |
| Zdroj: | Oncotarget, vol. 7, no. 24, pp. 36666-36680 Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.9134 |
| Popis: | The inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) by chemical inhibitors, such as rapamycin, has demonstrated anti-cancer activity in preclinical and clinical trials. Their efficacy is, however, limited and tumors eventually relapse through resistance formation. In this study, using two different cancer mouse models, we identify tumor hypoxia as a novel mechanism of resistance of cancer cells against mTORC1 inhibitors. Indeed, we show that the activity of mTORC1 is mainly restricted to the non-hypoxic tumor compartment, as evidenced by a mutually exclusive staining pattern of the mTORC1 activity marker pS6 and the hypoxia marker pimonidazole. Consequently, whereas rapamycin reduces cancer cell proliferation in non-hypoxic regions, it has no effect in hypoxic areas, suggesting that cancer cells proliferate independently of mTORC1 under hypoxia. Targeting the hypoxic tumor compartment by knockdown of carbonic anhydrase IX (CAIX) using short hairpin RNA or by chemical inhibition of CAIX with acetazolamide potentiates the anti-cancer activity of rapamycin. Taken together, these data emphasize that hypoxia impairs the anti-cancer efficacy of rapalogs. Therapeutic strategies targeting the hypoxic tumor compartment, such as the inhibition of CAIX, potentiate the efficacy of rapamycin and warrant further clinical evaluation. |
| Databáze: | OpenAIRE |
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