Akt and Autophagy Cooperate to Promote Survival of Drug-Resistant Glioma

Sci. Signal., 9 November 2010
Vol. 3, Issue 147, p. ra81
DOI: 10.1126/scisignal.2001017

Akt and Autophagy Cooperate to Promote Survival of Drug-Resistant Glioma

  1. Qi-Wen Fan1,2,3,4,
  2. Christine Cheng1,2,3,4,
  3. Chris Hackett1,2,3,4,
  4. Morri Feldman5,6,
  5. Benjamin T. Houseman5,6,
  6. Theodore Nicolaides1,2,3,4,
  7. Daphne Haas-Kogan3,4,
  8. C. David James3,
  9. Scott A. Oakes4,7,
  10. Jayanta Debnath4,7,
  11. Kevan M. Shokat5,6,8, and
  12. William A. Weiss1,2,3,4,*
  1. 1Department of Neurology, University of California, 1450 Third Street, MC0520, San Francisco, CA 94158–9001, USA.
  2. 2Department of Pediatrics, University of California, San Francisco, CA 94158–9001, USA.
  3. 3Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, CA 94158–9001, USA.
  4. 4Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158–9001, USA.
  5. 5Program in Chemistry and Chemical Biology, University of California, San Francisco, CA 94158–9001, USA.
  6. 6Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158–9001, USA.
  7. 7Department of Pathology, University of California, San Francisco, CA 94158–9001, USA.
  8. 8Howard Hughes Medical Institute, University of California, San Francisco, CA 94158–9001, USA.
  1. *To whom correspondence should be addressed. E-mail: weiss{at}cgl.ucsf.edu

Abstract

Although the phosphatidylinositol 3-kinase to Akt to mammalian target of rapamycin (PI3K-Akt-mTOR) pathway promotes survival signaling, inhibitors of PI3K and mTOR induce minimal cell death in PTEN (phosphatase and tensin homolog deleted from chromosome 10) mutant glioma. Here, we show that the dual PI3K-mTOR inhibitor PI-103 induces autophagy in a form of glioma that is resistant to therapy. Inhibitors of autophagosome maturation cooperated with PI-103 to induce apoptosis through the mitochondrial pathway, indicating that the cellular self-digestion process of autophagy acted as a survival signal in this setting. Not all inhibitors of mTOR synergized with inhibitors of autophagy. Rapamycin delivered alone induced autophagy, yet cells survived inhibition of autophagosome maturation because of rapamycin-mediated activation of Akt. In contrast, adenosine 5′-triphosphate–competitive inhibitors of mTOR stimulated autophagy more potently than did rapamycin, with inhibition of mTOR complexes 1 and 2 contributing independently to induction of autophagy. We show that combined inhibition of PI3K and mTOR, which activates autophagy without activating Akt, cooperated with inhibition of autophagy to cause glioma cells to undergo apoptosis. Moreover, the PI3K-mTOR inhibitor NVP-BEZ235, which is in clinical use, synergized with the lysosomotropic inhibitor of autophagy, chloroquine, another agent in clinical use, to induce apoptosis in glioma xenografts in vivo, providing a therapeutic approach potentially translatable to humans.

Citation:

Q.-W. Fan, C. Cheng, C. Hackett, M. Feldman, B. T. Houseman, T. Nicolaides, D. Haas-Kogan, C. D. James, S. A. Oakes, J. Debnath, K. M. Shokat, and W. A. Weiss, Akt and Autophagy Cooperate to Promote Survival of Drug-Resistant Glioma. Sci. Signal. 3, ra81 (2010).

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