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

Kamphorst, J. J. , Chung, M. K., Fan, J. and Rabinowitz, J. D. (2014) Quantitative analysis of acetyl-CoA production in hypoxic cancer cells reveals substantial contribution from acetate. Cancer and Metabolism, 2, 23. (doi: 10.1186/2049-3002-2-23) (PMID:25671109) (PMCID:PMC4322440)

Abstract

Background 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 13C-tracers and mass spectrometry, the sources of acetyl-CoA in hypoxia.<p></p> 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. 13C-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).<p></p> Conclusions Acetate is an important source of acetyl-CoA in hypoxia. Inhibition of acetate metabolism may impair tumor growth.<p></p>

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Kamphorst, Dr Jurre
• Authors: Kamphorst, J. J., Chung, M. K., Fan, J., and Rabinowitz, J. D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancer and Metabolism
• Publisher: BioMed Central
• ISSN: 2049-3002
• ISSN (Online): 2049-3002
• Copyright Holders: Copyright © 2014 The Authors
• First Published: First published in Cancer and Metabolism 2:23
• Publisher Policy: Reproduced under a Creative Commons License