Abstract
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.
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Abbreviations
- AVO:
-
acidic vesicular organelle
- HIF-1:
-
hypoxia-inducible factor-1
- AMPK:
-
5′-AMP-activated protein kinase
- LC3:
-
microtubule-associated protein-1 light chain 3
- MEF:
-
mouse embryo fibroblast
- mTOR:
-
mammalian target of rapamycin
- TSC:
-
tuberous sclerosis complex
- pVHL:
-
von Hippel-Lindau protein
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Acknowledgements
We are grateful to N Mizushima, D Kwiatkowski, and A Koong for cell lines and reagents. This work was funded by the NCI (NCD).
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Papandreou, I., Lim, A., Laderoute, K. et al. Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L. Cell Death Differ 15, 1572–1581 (2008). https://doi.org/10.1038/cdd.2008.84
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DOI: https://doi.org/10.1038/cdd.2008.84
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