Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L.
Macroautophagy (called autophagy hereafter) is a catabolic process activated by various types of stress, most notably by nutrient deprivation. The autophagic degradation of intracellular macromolecules provides metabolic support for the cell; however, this physiological process can also initiate a form of cell death (type 2 programmed cell death). Here we report that oxygen deprivation can activate the autophagic pathway in human cancer cell lines. We observed that hypoxia induced distinct cellular changes characteristic of autophagy such as an increase in cytoplasmic acidic vesicles, and processing and cellular localization of microtubule-associated protein-1 light chain 3. Oxygen deprivation-induced autophagy did not require nutrient deprivation, hypoxia-inducible factor-1 (HIF-1) activity, or expression of the HIF-1 target gene BNIP3 (Bcl-2 adenovirus E1a nineteen kilodalton interacting protein 3) or BNIP3L (BNIP3 like protein). Hypoxia-induced autophagy involved the activity of 5'-AMP-activated protein kinase (AMPK). Finally, we determined that cells lacking the autophagy gene ATG5 were unable to activate the autophagic machinery in hypoxia, had decreased oxygen consumption and increased glucose uptake under hypoxia, had increased survival in hypoxic environments, and exhibited accelerated growth as xenografted tumors. Together, these findings suggest that the autophagic degradation of cellular macromolecules contributes to the energetic balance governed by AMPK, and that suppression of autophagy in transformed cells can increase both resistance to hypoxic stress and tumorigenicity.
Papandreou
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I
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Lim
A L
AL
Laderoute
K
K
Denko
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NC
D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; C090121:BNIP3 protein, human; C116838:BNIP3L protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D000263:Adenylate Kinase; D010100:Oxygen