Targeting ACSS2 with a Transition-State Mimetic Inhibits Triple-Negative Breast Cancer Growth.

Autor:	Miller KD; Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, Pennsylvania., Pniewski K; Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, Pennsylvania., Perry CE; Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, Pennsylvania.; Cell & Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Papp SB; Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, Pennsylvania., Shaffer JD; Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, Pennsylvania.; Cell & Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Velasco-Silva JN; Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, Pennsylvania.; Biochemistry Department, School of Medicine, University of Utah, Salt Lake City, Utah., Casciano JC; Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, Pennsylvania., Aramburu TM; Gene Expression and Regulation Program, Wistar Institute, Philadelphia, Pennsylvania., Srikanth YVV; Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, Pennsylvania., Cassel J; Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, Pennsylvania., Skordalakes E; Gene Expression and Regulation Program, Wistar Institute, Philadelphia, Pennsylvania., Kossenkov AV; Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, Pennsylvania., Salvino JM; Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, Pennsylvania., Schug ZT; Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, Pennsylvania. zschug@wistar.org.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2021 Mar 01; Vol. 81 (5), pp. 1252-1264. Date of Electronic Publication: 2021 Jan 07.
DOI:	10.1158/0008-5472.CAN-20-1847
Abstrakt:	Acetyl-CoA is a vitally important and versatile metabolite used for many cellular processes including fatty acid synthesis, ATP production, and protein acetylation. Recent studies have shown that cancer cells upregulate acetyl-CoA synthetase 2 (ACSS2), an enzyme that converts acetate to acetyl-CoA, in response to stresses such as low nutrient availability and hypoxia. Stressed cancer cells use ACSS2 as a means to exploit acetate as an alternative nutrient source. Genetic depletion of ACSS2 in tumors inhibits the growth of a wide variety of cancers. However, there are no studies on the use of an ACSS2 inhibitor to block tumor growth. In this study, we synthesized a small-molecule inhibitor that acts as a transition-state mimetic to block ACSS2 activity in vitro and in vivo . Pharmacologic inhibition of ACSS2 as a single agent impaired breast tumor growth. Collectively, our findings suggest that targeting ACSS2 may be an effective therapeutic approach for the treatment of patients with breast cancer. SIGNIFICANCE: These findings suggest that targeting acetate metabolism through ACSS2 inhibitors has the potential to safely and effectively treat a wide range of patients with cancer. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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