The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid β-oxidation
Abstract
Activation of the oncogenic kinase Akt stimulates glucose uptake and metabolism in cancer cells and renders these cells susceptible to death in response to glucose withdrawal. Here we show that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) reverses the sensitivity of Akt-expressing glioblastoma cells to glucose deprivation. AICAR's protection depends on the activation of AMPK, as expression of a dominant-negative form of AMPK abolished this effect. AMPK is a cellular energy sensor whose activation can both block anabolic pathways such as protein synthesis and activate catabolic reactions such as fatty acid oxidation to maintain cellular bioenergetics. While rapamycin treatment mimicked the effect of AICAR on inhibiting markers of cap-dependent translation, it failed to protect Akt-expressing cells from death upon glucose withdrawal. Compared to control cells, Akt-expressing cells were impaired in the ability to induce fatty acid oxidation in response to glucose deprivation unless stimulated with AICAR. Stimulation of fatty acid oxidation was sufficient to maintain cell survival as activation of fatty acid oxidation with bezafibrate also protected Akt-expressing cells from glucose withdrawal-induced death. Conversely, treatment with a CPT-1 inhibitor to block fatty acid import into mitochondria prevented AICAR from stimulating fatty acid oxidation and promoting cell survival in the absence of glucose. Finally, cell survival did not require reversal of Akt's effects on either protein translation or lipid synthesis as the addition of the cell penetrant oxidizable substrate methyl-pyruvate was sufficient to maintain survival of Akt-expressing cells deprived of glucose. Together, these data suggest that activation of Akt blocks the ability of cancer cells to metabolize nonglycolytic bioenergetic substrates, leading to glucose addiction.
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Activated PI3K/Akt leads to enhanced glucose uptake and glycolysis.
“Activated PI3K/Akt leads to enhanced glucose uptake and glycolysis (Buzzai et al., 2005; Elstrom et al., 2004).”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Buzzai et al., 2005
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- Authors
- Buzzai, M., Bauer, D. E., Jones, R. G., DeBerardinis, R. J., Hatzivassiliou, G., Elstrom, R. L., & Thompson, C. B.
- Affiliations
- Abramson Cancer Center (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Thompson, Craig B
- Venue
- Oncogene
- Published
- 2005-04-04
- Volume
- 24
- Issue
- 26
- Pages
- 4165-4173
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W1964353872
- Cited by
- 357
- References
- 29
- Citations by year
- 2025: 8 · 2024: 6 · 2023: 11 · 2022: 11 · 2021: 13 · 2020: 14 · 2019: 27 · 2018: 16 · 2017: 17 · 2016: 19 · 2015: 15 · 2014: 35 · 2013: 23 · 2012: 34
- FWCI
- 5.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- University of Pennsylvania
- National Institutes of Health
- National Institute of General Medical Sciences (5T32-GM008638-08, T32GM008638)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- Akt, glucose deprivation, fatty acid beta-oxidation, AMPK, AICAR, glioblastoma, rapamycin, cap-dependent translation, bezafibrate, methyl pyruvate, cancer metabolism, energy sensing, cell survival
- MeSH terms
- Aminoimidazole Carboxamide, Cell Survival, Fatty Acids, Glioma, Glucose, Humans, Hypoglycemic Agents, Oxidation-Reduction, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Ribonucleotides, Tumor Cells, Cultured, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt
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