Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation
Open accessAbstract
The protumorigenic functions for autophagy are largely attributed to its ability to promote cancer cell survival in response to diverse stresses. Here we demonstrate an unexpected connection between autophagy and glucose metabolism that facilitates adhesion-independent transformation driven by a strong oncogenic insult—mutationally active Ras. In cells ectopically expressing oncogenic H-Ras as well as human cancer cell lines harboring endogenous K-Ras mutations, autophagy is induced following extracellular matrix detachment. Inhibiting autophagy due to the genetic deletion or RNA interference–mediated depletion of multiple autophagy regulators attenuates Ras-mediated adhesion-independent transformation and proliferation as well as reduces glycolytic capacity. Furthermore, in contrast to autophagy-competent cells, both proliferation and transformation in autophagy-deficient cells expressing oncogenic Ras are insensitive to reductions in glucose availability. Overall, increased glycolysis in autophagy-competent cells facilitates Ras-mediated adhesion-independent transformation, suggesting a unique mechanism by which autophagy may promote Ras-driven tumor growth in specific metabolic contexts.
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Oncogenic HRAS increases glycolytic rates including glucose uptake, indicating that increased aerobic glycolysis is essential for RAS-mutant tumors to match energy production with biosynthetic needs.
“Additionally, oncogenic HRAS mediates enhanced glycolytic rates including increased glucose uptake, underscoring the fact that increased aerobic glycolysis is essential for RAS-mutant tumors to match energy production with the requirement for enhanced biosynthetic pathways39.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [39]
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- Authors
- Lock, R., Roy, S., Kenific, C. M., Su, J. S., Salas, E., Ronen, S. M., & Debnath, J.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Debnath, Jayanta
- Venue
- Molecular Biology of the Cell
- Published
- 2011-01-15
- Volume
- 22
- Issue
- 2
- Pages
- 165-178
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC3020913
- OpenAlex
- W1996593753
- Cited by
- 467
- References
- 35
- Citations by year
- 2026: 3 · 2025: 20 · 2024: 12 · 2023: 17 · 2022: 32 · 2021: 41 · 2020: 27 · 2019: 33 · 2018: 35 · 2017: 31 · 2016: 39 · 2015: 32 · 2014: 42 · 2013: 43 · 2012: 31
- FWCI
- 23.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- Molecular Biology of the Cell (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA130819, R01CA126792)
- 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 › Metabolism, Diabetes, and Cancer
- Keywords
- autophagy, glycolysis, oncogenic Ras, glucose metabolism, extracellular matrix detachment, KRAS mutation, tumor cell proliferation, tumor growth
- MeSH terms
- Autophagy-Related Protein 12, Autophagy-Related Protein 7, Animals, Autophagy, Cell Adhesion, Cell Line, Transformed, Cell Transformation, Neoplastic, Female, Glycolysis, Humans, Tumor Cells, Cultured, ras Proteins, Proto-Oncogene Proteins c-bcl-2, Anoikis, Small Ubiquitin-Related Modifier Proteins, RNA Interference, Ubiquitin-Activating Enzymes, Cell Proliferation, Mice
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