Acetyl-CoA Synthetase 2 Promotes Acetate Utilization and Maintains Cancer Cell Growth under Metabolic Stress
2015; Cell Press; Volume: 27; Issue: 1 Linguagem: Inglês
10.1016/j.ccell.2014.12.002
ISSN1878-3686
AutoresZachary T. Schug, Barrie Peck, Dylan T. Jones, Zuo‐Feng Zhang, Shaun Grosskurth, Israt S. Alam, Louise Goodwin, Elizabeth A. Smethurst, Susan Mason, Karen Blyth, Lynn McGarry, Daniel James, Emma Shanks, Gabriela Kalna, Rebecca E. Saunders, Ming Jiang, Michael Howell, François Lassailly, May Zaw Thin, Bradley Spencer‐Dene, Gordon Stamp, Niels J. F. van den Broek, Gillian Mackay, Vinay Bulusu, Jurre J. Kamphorst, Saverio Tardito, David Strachan, Adrian L. Harris, Eric O. Aboagye, Susan E. Critchlow, Michael J.O. Wakelam, Almut Schulze, Eyal Gottlieb,
Tópico(s)Metabolomics and Mass Spectrometry Studies
ResumoHighlights•ACSS2 expression positively correlates with tumor stage and patient survival•Hypoxia and low lipid availability synergistically stimulate ACSS2 expression•Acetate is a major source of carbon for lipid synthesis during metabolic stress•ACSS2 is required for growth of tumor xenografts harboring ACSS2 copy-number gainsSummaryA 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.Graphical abstract
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