Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L
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…
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AMPK secures cellular energy balance under hypoxia by promoting autophagy independently of the HIF pathway.
“Furthermore, AMPK has been shown to secure cellular energy balance under hypoxia by promoting autophagy independently of the HIF pathway [198].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [198]
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- Authors
- Papandreou, I., Lim, A. L., Laderoute, K., & Denko, N. C.
- Affiliations
- Stanford Medicine (US)
- SRI International (US)
- Corresponding author
- Denko, N C
- Venue
- Cell Death & Differentiation
- Published
- 2008-06-13
- Volume
- 15
- Issue
- 10
- Pages
- 1572-1581
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- OpenAlex
- W1972553173
- Cited by
- 334
- References
- 1
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 9 · 2023: 6 · 2022: 25 · 2021: 20 · 2020: 14 · 2019: 21 · 2018: 14 · 2017: 10 · 2016: 24 · 2015: 26 · 2014: 22 · 2013: 30 · 2012: 23
- FWCI
- 19.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1s10od020006-01)
- National Cancer Institute (P01CA067166, R01CA163581, P30CA016058)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- hypoxia, autophagy, AMPK, oxygen deprivation, cancer cells, HIF-1, BNIP3, BNIP3L, ATG5, tumor growth, glucose uptake, oxygen consumption, tumorigenicity
- MeSH terms
- Autophagy-Related Protein 5, Adenylate Kinase, Animals, Hypoxia, Autophagy, Fibroblasts, Humans, Membrane Proteins, Microtubule-Associated Proteins, Oxygen, Phagosomes, Proto-Oncogene Proteins, Signal Transduction, Mice, Knockout, Tumor Suppressor Proteins, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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