Autophagy and Akt promote survival in glioma.
Signaling through phosphatidylinositol 3-kinase (PtdIns3K)-Akt-mTOR is frequently activated in cancers including glioblastoma multiforme (GBM), where this kinase network regulates survival. It is thus surprising that inhibitors of these pathways induce minimal cell death in glioma. We showed that the dual PtdIns3K-mTOR inhibitor PI-103 induces autophagy in therapy-resistant, PTEN-mutant glioma, with blockade of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) contributing independently to autophagy. Inhibition of autophagosome maturation synergizes with PI-103 to induce apoptosis through the Bax-dependent intrinsic mitochondrial pathway, indicating that PI-103 induces autophagy as a survival pathway in this setting. Not all inhibitors of PtdIns3K-Akt-mTOR signaling synergize with inhibitors of autophagy. The allosteric mTORC1 inhibitor rapamycin fails to induce apoptosis in conjunction with blockade of autophagy, due to feedback-activation of Akt. Apoptosis in the setting of rapamycin therapy requires concurrent inhibition of both autophagy and of PtdIns3K-Akt. Moreover, the clinical PtdIns3K-mTOR inhibitor NVP-BEZ235 cooperates with the clinical lysosomotropic autophagy inhibitor chloroquine to induce apoptosis in PTEN-mutant glioma xenografts in vivo, offering a therapeutic approach translatable to patients.
Department of Neurology, Neurological Surgery and Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
Qi-Wen
QW
Fan
William A
WA
Weiss
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001343:Autophagy / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005910:Glioma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008954:Models, Biological; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology
D047428:Protein Kinase Inhibitors; D051058:Oncogene Protein v-akt
Sci Signal. 2010 Nov 09;3(147):ra81
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