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Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation.

Cell metabolism (2018-08-28)
Ulrike Bruning, Francisco Morales-Rodriguez, Joanna Kalucka, Jermaine Goveia, Federico Taverna, Karla C S Queiroz, Charlotte Dubois, Anna Rita Cantelmo, Rongyuan Chen, Stefan Loroch, Evy Timmerman, Vanessa Caixeta, Katarzyna Bloch, Lena-Christin Conradi, Lucas Treps, An Staes, Kris Gevaert, Andrew Tee, Mieke Dewerchin, Clay F Semenkovich, Francis Impens, Birgit Schilling, Eric Verdin, Johannes V Swinnen, Jordan L Meier, Rhushikesh A Kulkarni, Albert Sickmann, Bart Ghesquière, Luc Schoonjans, Xuri Li, Massimiliano Mazzone, Peter Carmeliet
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.

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Roche
In Situ Cell Death Detection Kit, TMR red, sufficient for ≤50 tests