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Regulation of hypoxia-induced autophagy in glioblastoma involves ATG9A
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Journal Article
Regulation of hypoxia-induced autophagy in glioblastoma involves ATG9A
2017
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Angiogenesis Inhibitors - pharmacology
/ Animals
/ Autophagy-Related Proteins - metabolism
/ Autophagy-Related Proteins - physiology
/ Biomedical and Life Sciences
/ Brain Neoplasms - blood supply
/ Brain Neoplasms - drug therapy
/ Brain Neoplasms - metabolism
/ Cell Survival - drug effects
/ Humans
/ Hypoxia
/ Membrane Proteins - metabolism
/ Membrane Proteins - physiology
/ Mice
/ Molecular Targeted Therapy - methods
/ Neoplasm Proteins - metabolism
/ Neoplasm Proteins - physiology
/ Oncology
/ Spheroids, Cellular - pathology
/ Survival
/ Tumors
/ Vesicular Transport Proteins - metabolism
