title: Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma.
abstract: Antiangiogenic therapy leads to devascularization that limits tumor growth. However, the benefits of angiogenesis inhibitors are typically transient and resistance often develops. In this study, we explored the hypothesis that hypoxia caused by antiangiogenic therapy induces tumor cell autophagy as a cytoprotective adaptive response, thereby promoting treatment resistance. Hypoxia-induced autophagy was dependent on signaling through the hypoxia-inducible factor-1α (HIF-1α)/AMPK pathway, and treatment of hypoxic cells with autophagy inhibitors caused a shift from autophagic to apoptotic cell death in vitro. In glioblastomas, clinically resistant to the VEGF-neutralizing antibody bevacizumab, increased regions of hypoxia and higher levels of autophagy-mediating BNIP3 were found when compared with pretreatment specimens from the same patients. When treated with bevacizumab alone, human glioblastoma xenografts showed increased BNIP3 expression and hypoxia-associated growth, which could be prevented by addition of the autophagy inhibitor chloroquine. In vivo targeting of the essential autophagy gene ATG7 also disrupted tumor growth when combined with bevacizumab treatment. Together, our findings elucidate a novel mechanism of resistance to antiangiogenic therapy in which hypoxia-mediated autophagy promotes tumor cell survival. One strong implication of our findings is that autophagy inhibitors may help prevent resistance to antiangiogenic therapy used in the clinic.
authors.affiliation: University of California at San Francisco Neurosurgery, San Francisco, California 94158, USA.
authors.forename: Yu-Long
authors.initials: YL
authors.lastname: Hu
authors.forename: Michael
authors.initials: M
authors.lastname: DeLay
authors.forename: Arman
authors.initials: A
authors.lastname: Jahangiri
authors.forename: Annette M
authors.initials: AM
authors.lastname: Molinaro
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Rose
authors.forename: W Shawn
authors.initials: WS
authors.lastname: Carbonell
authors.forename: Manish K
authors.initials: MK
authors.lastname: Aghi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology; D000222:Adaptation, Physiological; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D001343:Autophagy / Q000502:physiology*; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival; D002738:Chloroquine / Q000494:pharmacology; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D008565:Membrane Proteins / Q000032:analysis; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000032:analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C090121:BNIP3 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D000068258:Bevacizumab; D002738:Chloroquine; D055372:AMP-Activated Protein Kinases