期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：11
DOI：10.1073/pnas.2117013119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
The study provided a long-sought molecular mechanism that could explain the link between fatty acid metabolism and cancer metastasis. Further understanding may lead to new strategies to inhibit cancer metastasis. The chemical proteomic approach developed here will be useful for discovering other regulatory mechanisms of protein function by small molecule metabolites.
Fatty acid metabolism has well-established connections to cancer progression and metastasis. However, whether the metabolic intermediates of fatty acid metabolism regulate this process through protein–metabolite interactions remains largely unknown. Here, we investigated whether long-chain fatty acyl coenzyme A (LCFA-CoA), an important metabolic intermediate involved in fatty acid metabolism, could regulate cellular protein functions to affect cancer. We used a quantitative chemical proteomic approach to identify proteins that could be regulated by LCFA-CoA. This strategy identified NME1 and NME2 as potential targets regulated by LCFA-CoA. In vitro, LCFA-CoA potently inhibited NME1/2. In cells, LCFA-CoA inhibited clathrin-mediated endocytosis and cancer cell migration, processes regulated by NME1/2. In vivo, NME1, a known metastasis suppressor, is inhibited by LCFA-CoA, and its metastasis suppressor function is compromised in mouse models of breast cancer specifically under high-fat–diet conditions. Thus, inhibition of NME1 by LCFA-CoA provides a molecular mechanism linking fatty acid metabolism and cancer metastasis, demonstrating the power of the chemical proteomic approach for discovering regulatory roles of metabolites.
