Identifying the Unknown Carbon Source for Acetyl-CoA Production in Cancer Cells Under Hypoxia

Abstract

Hypoxia, or low-oxygen conditions, is relevant to tumor growth because tumors often grow densely and far away from blood vessels. In normoxia, glucose and glutamine are the only sources for acetyl-CoA production, whereas in hypoxia, there is a third unknown source that accounts for 50% of acetyl-CoA production. In this study, the unknown source was elucidated using \(^{13}\)C-labeling experiments and analysis of metabolites using liquid chromatography - mass spectrometry (LC-MS). Surprisingly, the main carbon sources in the growth media, namely amino acids and fatty acids, were not the source. It was found that acetate is the source via conversion by both mitochondrial and cytosolic acetyl-CoA synthetases to acetyl-CoA. Upon inhibition of these enzymes, cell growth in hypoxia was inhibited. The enzymes were also overexpressed in hypoxia. The importance of ACSS1 and ACSS2 in cancer cell metabolism under hypoxia can be exploited in anti-cancer therapy.