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Impairment of angiogenesis by fatty acid synthase inhibition Involves mTOR malonylation

Bruning, Ulrike, Morales-Rodriguez, Francisco, Kalucka, Joanna, Goveia, Jermaine, Taverna, Federico, Queiroz, Karla C.S., Dubois, Charlotte, Cantelmo, Anna Rita, Chen, Rongyuan, Loroch, Stefan, Timmerman, Evy, Caixeta, Vanessa, Bloch, Katarzyna, Conradi, Lena-Christin, Treps, Lucas, Staes, An, Gevaert, Kris, Tee, Andrew, Dewerchin, Mieke, Semenkovich, Clay F., Impens, Francis, Schilling, Birgit, Verdin, Eric, Swinnen, Johannes V., Meier, Jordan L., Kulkarni, Rhushikesh A., Sickmann, Albert, Ghesquière, Bart, Schoonjans, Luc, Li, Xuri, Mazzone, Massimiliano and Carmeliet, Peter 2018. Impairment of angiogenesis by fatty acid synthase inhibition Involves mTOR malonylation. Cell Metabolism 28 (6) , pp. 866-880. 10.1016/j.cmet.2018.07.019

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Elsevier
ISSN: 1550-4131
Date of First Compliant Deposit: 17 December 2018
Date of Acceptance: 27 July 2018
Last Modified: 27 Nov 2020 08:56
URI: http://orca-mwe.cf.ac.uk/id/eprint/117702

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