Akt and autophagy cooperate to promote survival of drug-resistant glioma.
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.
Department of Neurology, University of California, 1450 Third Street, MC0520, San Francisco, CA 94158-9001, USA.
Qi-Wen
QW
Fan
Christine
C
Cheng
Chris
C
Hackett
Morri
M
Feldman
Benjamin T
BT
Houseman
Theodore
T
Nicolaides
Daphne
D
Haas-Kogan
C David
CD
James
Scott A
SA
Oakes
Jayanta
J
Debnath
Kevan M
KM
Shokat
William A
WA
Weiss
D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000378:metabolism / Q000494:pharmacology; D004357:Drug Synergism; D005434:Flow Cytometry; D005663:Furans / Q000494:pharmacology*; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D006652:Histological Techniques; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011804:Quinolines / Q000378:metabolism / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014183:Transplantation, Heterologous
D005663:Furans; D007093:Imidazoles; C522973:PI103; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011804:Quinolines; D002738:Chloroquine; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C531198:dactolisib; D020123:Sirolimus