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Autophagy and Akt promote survival in glioma

Qi-Wen Fan1, William A Weiss

  • 1Department of Neurology, Neurological Surgery and Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.

Autophagy
|January 27, 2011
PubMed

Insights

Inhibiting the phosphatidylinositol 3-kinase (PtdIns3K)-Akt-mTOR pathway in glioblastoma multiforme (GBM) activates autophagy. Combining autophagy inhibition with PtdIns3K-mTOR blockade induces apoptosis, offering a potential therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling Pathways

Background:

  • The phosphatidylinositol 3-kinase (PtdIns3K)-Akt-mTOR signaling pathway is crucial for cancer cell survival, frequently activated in glioblastoma multiforme (GBM).
  • Despite frequent activation, PtdIns3K-Akt-mTOR inhibitors show limited efficacy in inducing cell death in glioma, suggesting compensatory survival mechanisms.

Purpose of the Study:

  • To investigate the role of autophagy in therapy-resistant, PTEN-mutant glioma treated with PtdIns3K-mTOR inhibitors.
  • To determine if inhibiting autophagy synergizes with PtdIns3K-Akt-mTOR inhibitors to induce apoptosis in glioma.

Main Methods:

  • Utilized the dual PtdIns3K-mTOR inhibitor PI-103 in PTEN-mutant glioma models.
  • Assessed the induction of autophagy and its contribution to cell survival upon PI-103 treatment.
  • Investigated the synergistic effects of combining PI-103 with autophagy inhibition on apoptosis induction.
  • Evaluated the efficacy of combining clinical PtdIns3K-mTOR inhibitor NVP-BEZ235 with chloroquine in PTEN-mutant glioma xenografts.

Main Results:

  • The dual PtdIns3K-mTOR inhibitor PI-103 induced autophagy in PTEN-mutant glioma, with blockade of both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) contributing independently.
  • Inhibition of autophagosome maturation synergized with PI-103 to induce apoptosis via the Bax-dependent intrinsic mitochondrial pathway, indicating autophagy acts as a survival mechanism.
  • The mTORC1 inhibitor rapamycin failed to induce apoptosis with autophagy blockade due to feedback-activation of Akt.
  • Concurrent inhibition of autophagy and PtdIns3K-Akt was required for apoptosis with rapamycin.
  • The clinical inhibitor NVP-BEZ235 combined with chloroquine induced apoptosis in PTEN-mutant glioma xenografts.

Conclusions:

  • Autophagy is induced as a survival mechanism by PtdIns3K-mTOR inhibitors in PTEN-mutant glioma.
  • Combining PtdIns3K-mTOR inhibitors with autophagy inhibitors synergistically induces apoptosis in glioma.
  • The combination of NVP-BEZ235 and chloroquine presents a promising therapeutic strategy for PTEN-mutant glioma.

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