Article (Scientific journals)
Regulation of hypoxia-induced autophagy in glioblastoma involves ATG9A.
Abdul Rahim, Siti Aminah; Dirkse, Anne; Oudin, Anais et al.
2017In British Journal of Cancer, 117 (6), p. 813-825
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Keywords :
Angiogenesis Inhibitors; ATG9A protein, human; Autophagy-Related Proteins; Membrane Proteins; Neoplasm Proteins; Vesicular Transport Proteins; 2S9ZZM9Q9V (Bevacizumab); 886U3H6UFF (Chloroquine); Angiogenesis Inhibitors/pharmacology; Animals; Autophagy/drug effects/physiology; Autophagy-Related Proteins/metabolism/physiology; Bevacizumab/pharmacology; Brain Neoplasms/blood supply/drug therapy/metabolism; Cell Line, Tumor; Cell Survival/drug effects/physiology; Chloroquine/pharmacology; Drug Synergism; Gene Expression Profiling; Gene Knockdown Techniques; Gene Silencing; Glioblastoma/blood supply/drug therapy/metabolism; Heterografts; Humans; Membrane Proteins/metabolism/physiology; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy/methods; Neoplasm Proteins/metabolism/physiology; Neoplasm Transplantation; Random Allocation; Spheroids, Cellular/pathology; Tumor Hypoxia/physiology; Vesicular Transport Proteins/metabolism/physiology
Abstract :
[en] 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.
Disciplines :
Oncology
Author, co-author :
Abdul Rahim, Siti Aminah;  NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg.
Dirkse, Anne;  NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg. ; Faculty of Science, Technology and Communication, University of Luxembourg, Esch-sur-Alzette L-4365, Luxembourg.
Oudin, Anais;  NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg.
Schuster, Anne;  NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg.
BOHLER, Jill ;  NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg.
Barthelemy, Vanessa;  NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg.
Muller, Arnaud;  Proteome and Genome Research Unit, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg.
Vallar, Laurent;  Proteome and Genome Research Unit, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg.
JANJI, Bassam ;  Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg.
GOLEBIEWSKA, Anna ;  NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg.
NICLOU, Simone P. ;  NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg. ; KG Jebsen Brain Tumour Research Center, Department of Biomedicine, University of Bergen, N-5019 Bergen, Norway.
External co-authors :
yes
Language :
English
Title :
Regulation of hypoxia-induced autophagy in glioblastoma involves ATG9A.
Publication date :
05 September 2017
Journal title :
British Journal of Cancer
ISSN :
0007-0920
eISSN :
1532-1827
Publisher :
Nature Publishing Group, United Kingdom
Volume :
117
Issue :
6
Pages :
813-825
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBilu :
since 27 February 2024

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