Acetate is a bioenergetic substrate for human glioblastoma and brain metastases
Open accessAbstract
Glioblastomas and brain metastases are highly proliferative brain tumors with short survival times. Previously, using (13)C-NMR analysis of brain tumors resected from patients during infusion of (13)C-glucose, we demonstrated that there is robust oxidation of glucose in the citric acid cycle, yet glucose contributes less than 50% of the carbons to the acetyl-CoA pool. Here, we show that primary and metastatic mouse orthotopic brain tumors have the capacity to oxidize [1,2-(13)C]acetate and can do so while simultaneously oxidizing [1,6-(13)C]glucose. The tumors do not oxidize [U-(13)C]glutamine. In vivo oxidation of [1,2-(13)C]acetate was validated in brain tumor patients and was correlated with expression of acetyl-CoA synthetase enzyme 2, ACSS2. Together, the data demonstrate a strikingly common metabolic phenotype in diverse brain tumors that includes the ability to oxidize acetate in the citric acid cycle. This adaptation may be important for meeting the high biosynthetic and bioenergetic demands of malignant growth.
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In glioblastoma tumors resected from patients, up to half of the intramitochondrial acetyl-CoA pool is derived from circulating acetate.
“The relevance of acetate as a potential fuel source has also been observed in vivo: in glioblastoma tumors resected from patients, up to half of the intramitochondrial acetyl-CoA pool is derived from circulating acetate (70).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [70]
Some cancer types, including liver and glioblastomas, readily take up acetate, which can be converted to acetyl-CoA by ACSS and undergo oxidation in the TCA cycle.
“Some cancer types, including liver and glioblastomas, readily take up acetate, which can be converted to acetyl-CoA by ACSS and undergo oxidation in the TCA cycle (70, 195).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [70]
Extracellular acetate is utilized by some cancers as source of acetyl-CoA for biosynthesis.
“Finally, extracellular acetate has recently been shown to be utilized by some cancers as a source of acetyl-CoA for biosynthesis.”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Mashimo et al., 2014
Brain tumor types including primary glioblastomas and brain metastases assimilate exogenous acetate and incorporate acetate-derived carbons into de novo synthesized fatty acids.
“Specifically, a variety of tumor types localized to the brain, including primary glioblastomas as well as brain metastases that originated from other tissues, have been shown to assimilate exogenous acetate and incorporate acetate-derived carbons into de novo synthesized fatty acids (Comerford et al., 2014; Mashimo et al., 2014; Schug et al., 2015).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Mashimo et al., 2014
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- Authors
- Mashimo, T., Pichumani, K., Vemireddy, V., Hatanpaa, K. J., Singh, D. K., Sirasanagandla, S., Nannepaga, S., Piccirillo, S. G., Kovacs, Z., Foong, C., Huang, Z., Barnett, S., Mickey, B. E., DeBerardinis, R. J., Tu, B. P., Maher, E. A., & Bachoo, R. M.
- Affiliations
- Harold C. Simmons Comprehensive Cancer Center (US)
- The University of Texas Southwestern Medical Center (US)
- Children's Medical Center (US)
- Corresponding author
- Maher, Elizabeth A.
- Bachoo, Robert M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 159
- Issue
- 7
- Pages
- 1603-1614
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4374602
- OpenAlex
- W1992524428
- Cited by
- 760
- References
- 41
- Citations by year
- 2026: 32 · 2025: 69 · 2024: 64 · 2023: 64 · 2022: 88 · 2021: 77 · 2020: 66 · 2019: 64 · 2018: 53 · 2017: 69 · 2016: 71 · 2015: 41 · 2014: 2
- FWCI
- 19.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA154843, R01CA157996, P30CA142543)
- National Institute of Neurological Disorders and Stroke (R01NS065195)
- National Institute of Biomedical Imaging and Bioengineering (P41EB015908, EB 015908)
- Topics
- 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
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- acetate oxidation, glioblastoma, brain metastases, TCA cycle, acetyl-CoA, ACSS2, acetyl-CoA synthetase 2, glucose oxidation, cancer metabolism, 13C NMR, glutamine metabolism, tumor bioenergetics
- MeSH terms
- Acetates, Acetate-CoA Ligase, Animals, Brain Neoplasms, Citric Acid Cycle, Disease Models, Animal, Glioblastoma, Humans, Neoplasm Metastasis, Glutamic Acid, Mice
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