Acetyl-CoA Synthetase 2 Promotes Acetate Utilization and Maintains Cancer Cell Growth under Metabolic Stress

Abstract

SummaryA functional genomics study revealed that the activity of acetyl-CoA synthetase 2 (ACSS2) contributes to cancer cell growth under low-oxygen and lipid-depleted conditions. Comparative metabolomics and lipidomics demonstrated that acetate is used as a nutritional source by cancer cells in an ACSS2-dependent manner, and supplied a significant fraction of the carbon within the fatty acid and phospholipid pools. ACSS2 expression is upregulated under metabolically stressed conditions and ACSS2 silencing reduced the growth of tumor xenografts. ACSS2 exhibits copy-number gain in human breast tumors, and ACSS2 expression correlates with disease progression. These results signify a critical role for acetate consumption in the production of lipid biomass within the harsh tumor microenvironment.

De novo acetate production is coupled to central carbon metabolism in mammals

“…5g and 5h) and isotope tracing with deuterated acetaldehyde confirmed that ACLY knockdown cells exhibited increased acetate utilization which could be further increased by limiting nutrient availability during serum starvation (Fig. 5i), which is consistent with previous findings 10,34 . Thus these experiments confirm that de novo pyruvate-derived acetate production can have critical functional roles in supporting acetyl-CoA metabolism.…”

“…The dependence on acetate to supply both nucleocytosolic and mitochondrial acetyl-CoA pools has been identified in multiple cell types, including cancer cells, T cells, and neurons [8][9][10]13,14 . Our study provides evidence for a glucose-derived overflow pathway for acetate metabolism that occurs in mammalian cells.…”

“…Acetate metabolism provides a parallel pathway for acetylcoA production separate from conversion of citrate to acetyl-CoA by ATP citrate lyase (ACLY) and thus acetate allows for protein acetylation and lipogenesis independent of citrate conversation to acetyl-CoA. This pathway is essential in nutrient deprived tumor microenvironments and other diverse contexts but the origin of acetate has been unclear [8][9][10][11][12][13][14] . It has been postulated that acetate may be synthesized de novo in cells [15][16][17][18][19] but the pathways and quantitative reaction mechanisms through which this may occur are unknown.…”

Bonded Cumomer Analysis of Human Melanoma Metabolism Monitored by 13C NMR Spectroscopy of Perfused Tumor Cells

“…However, this does not include possible direct contributions from unlabeled glutamine (i.e. through cytosolic reductive carboxylation by isocitrate dehydrogenase IDH1 or mitochondrial IDH2) and potentially from the cytosolic acetyl-CoA synthetase 2 (ACSS2) reaction (50).…”

Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets

“…[3][4][5] Although the initial focus of this field has been aerobic glycolysis (the Warburg effect), 6 increasing evidence points to a complex landscape of tumor metabolic circuitries beyond aerobic glycolysis, including varied contribution of mitochondria to tumor metabolism as well as heterogeneity in fuel utilization pathways. [7][8][9][10][11][12] Diffuse large B-cell lymphomas (DLBCLs) are a genetically heterogeneous group of tumors that can be classified into distinct molecular subtypes based on gene expression profiles. The cell-of-origin (COO) classification defined DLBCL subsets that shared certain components of their RNA profiles with normal germinal center B cells (GCBs) or in vitroactivated B cells (ABCs), and a third undefined subset designated 'type 3'.…”