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Quantitative analysis of acetyl-CoA production in hypoxic cancer cells reveals substantial contribution from acetate.

AbstractBACKGROUND:
Cell growth requires fatty acids for membrane synthesis. Fatty acids are assembled from 2-carbon units in the form of acetyl-CoA (AcCoA). In nutrient and oxygen replete conditions, acetyl-CoA is predominantly derived from glucose. In hypoxia, however, flux from glucose to acetyl-CoA decreases, and the fractional contribution of glutamine to acetyl-CoA increases. The significance of other acetyl-CoA sources, however, has not been rigorously evaluated. Here we investigate quantitatively, using (13)C-tracers and mass spectrometry, the sources of acetyl-CoA in hypoxia.
RESULTS:
In normoxic conditions, cultured cells produced more than 90% of acetyl-CoA from glucose and glutamine-derived carbon. In hypoxic cells, this contribution dropped, ranging across cell lines from 50% to 80%. Thus, under hypoxia, one or more additional substrates significantly contribute to acetyl-CoA production. (13)C-tracer experiments revealed that neither amino acids nor fatty acids are the primary source of this acetyl-CoA. Instead, the main additional source is acetate. A large contribution from acetate occurs despite it being present in the medium at a low concentration (50-500 μM).
CONCLUSIONS:
Acetate is an important source of acetyl-CoA in hypoxia. Inhibition of acetate metabolism may impair tumor growth.
AuthorsJurre J Kamphorst, Michelle K Chung, Jing Fan, Joshua D Rabinowitz
JournalCancer & metabolism (Cancer Metab) Vol. 2 Pg. 23 ( 2014) ISSN: 2049-3002 [Print] England
PMID25671109 (Publication Type: Journal Article)

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