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Autophagy is essential for tumor development and survival in hypoxia and in vivo in glioblastoma. (Provisional)

ABSTRACT: Hypoxia is negatively associated with glioblastoma patient survival and contributes strongly to tumor resistance. Unfortunately novel anti-angiogenic therapy increases hypoxia and activates survival pathways in tumor cells leading to inevitable tumor relapse. Here we demonstrate that primary glioma cultures and cell lines depend on autophagy to survive severe hypoxia but also at normal oxygen levels. Positive regulators of autophagy are expressed at higher levels in tumor cells and induction in severe hypoxia is more prominent compared to normal brain cells. We demonstrate that autophagy is an essential/critical target for novel treatment in glioblastoma. We show ATG9A is induced by severe hypoxia and could be a novel player of the autophagic response in glioma cells. ATG9A targeting inhibited tumor growth, suggesting an essential role in glioma cell survival in vivo. While autophagy induction was also observed in normal astrocytes, glioma cells displayed a higher sensitivity towards autophagy inhibitors. Importantly, patient-derived cultures exhibited varying sensitivity towards anti-autophagy treatment, where certain cultures were dependent on autophagy already in normoxic conditions. The treatment of tumor bearing mice with the autophagy inhibitor chloroquine significantly increased mice survival, but combination treatment of the agent with bevacizumab did not reveal additive or synergistic effect. The present study demonstrates that inhibition of autophagy using chloroquine as a single agent provides a novel treatment strategy against glioblastoma. It remains to be seen whether autophagy inhibition will improve current standard of care treatment of newly diagnosed glioblastoma patients and whether more specific inhibitors will lead to stronger therapeutic outcome. (Provisional)

ORGANISM(S): Homo sapiens  

SUBMITTER: Arnaud Muller  

PROVIDER: E-MTAB-3085 | ArrayExpress | 2015-11-10


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E-MTAB-3085.idf.txt Idf
E-MTAB-3085.idf.txt_original Idf Raw
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Comprehensive analysis of glycolytic enzymes as therapeutic targets in the treatment of glioblastoma.

Sanzey Morgane M   Abdul Rahim Siti Aminah SA   Oudin Anais A   Dirkse Anne A   Kaoma Tony T   Vallar Laurent L   Herold-Mende Christel C   Bjerkvig Rolf R   Golebiewska Anna A   Niclou Simone P SP  

PloS one 20150501 5

Major efforts have been put in anti-angiogenic treatment for glioblastoma (GBM), an aggressive and highly vascularized brain tumor with dismal prognosis. However clinical outcome with anti-angiogenic agents has been disappointing and tumors quickly develop escape mechanisms. In preclinical GBM models we have recently shown that bevacizumab, a blocking antibody against vascular endothelial growth factor, induces hypoxia in treated tumors, which is accompanied by increased glycolytic activity and  ...[more]

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