| Autor: |
Abdul Rahim, Siti Aminah, Dirkse, Anne, Oudin, Anais, Schuster, Anne, Bohler, Jill, Barthelemy, Vanessa, Muller, Arnaud, Vallar, Laurent, Janji, Bassam, Golebiewska, Anna, Niclou, Simone P |
| Předmět: |
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| Zdroj: |
British Journal of Cancer; 9/5/2017, Vol. 117 Issue 6, p813-825, 13p, 4 Graphs |
| Abstrakt: |
Background: Hypoxia is negatively associated with glioblastoma (GBM) patient survival and contributes to tumour resistance. Anti-angiogenic therapy in GBM further increases hypoxia and activates survival pathways. The aim of this study was to determine the role of hypoxia-induced autophagy in GBM.Methods: Pharmacological inhibition of autophagy was applied in combination with bevacizumab in GBM patient-derived xenografts (PDXs). Sensitivity towards inhibitors was further tested in vitro under normoxia and hypoxia, followed by transcriptomic analysis. Genetic interference was done using ATG9A-depleted cells.Results: We find that GBM cells activate autophagy as a survival mechanism to hypoxia, although basic autophagy appears active under normoxic conditions. Although single agent chloroquine treatment in vivo significantly increased survival of PDXs, the combination with bevacizumab resulted in a synergistic effect at low non-effective chloroquine dose. ATG9A was consistently induced by hypoxia, and silencing of ATG9A led to decreased proliferation in vitro and delayed tumour growth in vivo. Hypoxia-induced activation of autophagy was compromised upon ATG9A depletion.Conclusions: This work shows that inhibition of autophagy is a promising strategy against GBM and identifies ATG9 as a novel target in hypoxia-induced autophagy. Combination with hypoxia-inducing agents may provide benefit by allowing to decrease the effective dose of autophagy inhibitors. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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