Acetate is a Bioenergetic Substrate for Human Glioblastoma and Brain Metastases

By T. Mashimo, K. Pichumani, Vamsidhara Vemireddy, K. Hatanpaa, D. K. Singh, Shyam Sirasanagandla, Suraj Nannepaga, S. Piccirillo, Z. Kovács, C. Foong and 7 more. Cell, 2014

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Glioblastomas and brain metastases are highly proliferative brain tumors with short survival times. Previously, using 13C-NMR analysis of brain tumors resected from patients during infusion of 13C-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 [1,2-13C]acetate and can do so simultaneously with [1,6-13C]glucose oxidation. The tumors do not oxidize [U-13C]glutamine. In vivo oxidation of [1,2-13C]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.

Subfields: Cancer Research, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2d8d61c9701367a515eef7c5d6d56dc28873b315

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Citations in the corpus

Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics (2017, background): “…but include abnormalities of hepatocyte metabolism, hepatocyte autophagy, and endoplasmic reticulum stress, hepatic immune cell function, adipose tissue inflammation, and systemic inflammatory mediators (Fabbrini et al., 2009; Masuoka and Chalasani, 2013; Targher et al., 2010; Yang et al., 2010).”
Mitochondrial metabolism and cancer (2017, background): “This involves not only increased uptake of glucose (a fraction of which is redirected to the pentose phosphate pathway (PPP) for nucleic acid synthesis and glutathione reduction) [70], but also the ability to process glutamine oxidatively (for energy production via the Krebs cycle and the ETC) or re”
Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “ACSS2 expression is required for the incorporation of 13C-acetate into glutamate and is positively correlated with the malignancy of GBM (Lyssiotis and Cantley, 2014; Mashimo et al., 2014).”
Lactate metabolism in human lung tumors (2017, positive): “The metabolic fates of glucose in FDG-PET-positive tumors and the extent to which other fuels complement glucose utilization in these tumors are areas of active study (Davidson et al., 2016; Fan et al., 2009; Hensley et al., 2016; Mashimo et al., 2014).”
Acetyl coenzyme A: a central metabolite and second messenger. (2015, background): “Moreover, elevated ACSS2 levels are associated with high tumor grade and dismal disease outcome in patients with human gliomas (Mashimo et al., 2014) and triple-negative breast carci-”
Targeting Metabolism for Cancer Therapy (2017, background): “Cancer cells are also able to generate acetyl-CoA from cytosolic acetate (Comerford et al., 2014; Gao et al., 2016; Kamphorst et al., 2014; Mashimo et al., 2014).”
Lipid metabolism reprogramming and its potential targets in cancer (2018, background): “Studies with patient-derived glioblastoma xenografts have shown that acetate contributes to acetyl-CoA synthesis in tumors [73].”
From Krebs to Clinic: Glutamine Metabolism to Cancer Therapy (2016, background): “BPTES inhibition of hGA(124-551), a truncated form of human kidneytype glutaminase.”