Targeting ACSS2 with a Transition-State Mimetic Inhibits Triple-Negative Breast Cancer Growth
- 7 January 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (5), 1252-1264
- https://doi.org/10.1158/0008-5472.can-20-1847
Abstract
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. Pharmacological 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.Keywords
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Funding Information
- NIH NCI (DP2 CA249950-01)
- Susan G. Komen (CCR19608782)
- NIH NCI (T32 CA009171)
- NIH (P30 CA010815)
- NIH (R50 CA221838, S10 OD023586)
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