The DOI matches its Crossref record; 62 of the 62 references it cites were found in a registry or an index.
Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation
Open accessAbstract
SUMMARY The role of fatty acid synthesis in endothelial cells (ECs) remains incompletely characterized. We report that fatty acid synthase knockdown (FASNKD) in ECs impedes vessel sprouting by reducing proliferation. Endothelial loss of FASN impaired angiogenesis in vivo, while FASN blockade reduced pathological ocular neovascularization, at >10-fold lower doses than used for anti-cancer treatment. Impaired angiogenesis was not due to energy stress, redox imbalance, or palmitate depletion. Rather, FASNKD elevated malonyl-CoA levels, causing malonylation (a post-translational modification) of mTOR at lysine 1218 (K1218). mTOR K-1218 malonylation impaired mTOR complex 1 (mTORC1) kinase activity, thereby reducing phosphorylation of downstream targets (p70S6K/4EBP1). Silencing acetyl-CoA carboxylase 1 (an enzyme producing malonyl-CoA) normalized malonyl-CoA levels and reactivated mTOR in FASNKD ECs. Mutagenesis unveiled the importance of mTOR K1218 malonylation for angiogenesis. This study unveils a novel role of FASN in metabolite signaling that contributes to explaining the anti-angiogenic effect of FASN blockade.
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Metadata
- Authors
- Bruning, U., Morales-Rodriguez, F., Kalucka, J., Goveia, J., Taverna, F., Queiroz, K. C. S., Dubois, C., Cantelmo, A. R., Chen, R., Loroch, S., Timmerman, E., Caixeta, V., Bloch, K., Conradi, L.-C., Treps, L., Staes, A., Gevaert, K., Tee, A., Dewerchin, M., Semenkovich, C. F., Impens, F., Schilling, B., Verdin, E., Swinnen, J. V., Meier, J. L., Kulkarni, R. A., Sickmann, A., Ghesquière, B., Schoonjans, L., Li, X., Mazzone, M., & Carmeliet, P.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 28
- Issue
- 6
- Pages
- 866-880.e15
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2888447333
- Cited by
- 282
- References
- 62
- FWCI
- 5.22
- Type
- journal article
- Language
- en
- Open access
- bronze
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- The paper
- Bruning, U., Morales-Rodriguez, F., Kalucka, J., Goveia, J., Taverna, F., Queiroz, K. C. S., Dubois, C., Cantelmo, A. R., Chen, R., Loroch, S., Timmerman, E., Caixeta, V., Bloch, K., Conradi, L.-C., Treps, L., Staes, A., Gevaert, K., Tee, A., Dewerchin, M., . . . Carmeliet, P. (2018). Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation. Cell Metabolism. https://doi.org/10.1016/j.cmet.2018.07.019
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
