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Impairment of angiogenesis by fatty acid synthase inhibition involves mTOR malonylation

(2018) CELL METABOLISM. 28(6). p.866-880
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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 (FASN(KD)) 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, FASN(KD) 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 FASN(KD) 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.
Keywords
LYSINE MALONYLATION, CANCER-CELLS, TUMOR, ACETYLATION, METABOLISM, GROWTH, CARCINOMA, OVEREXPRESSION, STOICHIOMETRY, LIPOGENESIS

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Citation

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MLA
Bruning, Ulrike, et al. “Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves MTOR Malonylation.” CELL METABOLISM, vol. 28, no. 6, 2018, pp. 866–80, doi:10.1016/j.cmet.2018.07.019.
APA
Bruning, U., Morales-Rodriguez, F., Kalucka, J., Goveia, J., Taverna, F., Queiroz, K. C., … Carmeliet, P. (2018). Impairment of angiogenesis by fatty acid synthase inhibition involves mTOR malonylation. CELL METABOLISM, 28(6), 866–880. https://doi.org/10.1016/j.cmet.2018.07.019
Chicago author-date
Bruning, Ulrike, Francisco Morales-Rodriguez, Joanna Kalucka, Jermaine Goveia, Federico Taverna, Karla CS Queiroz, Charlotte Dubois, et al. 2018. “Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves MTOR Malonylation.” CELL METABOLISM 28 (6): 866–80. https://doi.org/10.1016/j.cmet.2018.07.019.
Chicago author-date (all authors)
Bruning, Ulrike, Francisco Morales-Rodriguez, Joanna Kalucka, Jermaine Goveia, Federico Taverna, Karla CS 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, and Peter Carmeliet. 2018. “Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves MTOR Malonylation.” CELL METABOLISM 28 (6): 866–880. doi:10.1016/j.cmet.2018.07.019.
Vancouver
1.
Bruning U, Morales-Rodriguez F, Kalucka J, Goveia J, Taverna F, Queiroz KC, et al. Impairment of angiogenesis by fatty acid synthase inhibition involves mTOR malonylation. CELL METABOLISM. 2018;28(6):866–80.
IEEE
[1]
U. Bruning et al., “Impairment of angiogenesis by fatty acid synthase inhibition involves mTOR malonylation,” CELL METABOLISM, vol. 28, no. 6, pp. 866–880, 2018.
@article{8581647,
  abstract     = {{The role of fatty acid synthesis in endothelial cells (ECs) remains incompletely characterized. We report that fatty acid synthase knockdown (FASN(KD)) 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, FASN(KD) 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 FASN(KD) 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.}},
  author       = {{Bruning, Ulrike and Morales-Rodriguez, Francisco and Kalucka, Joanna and Goveia, Jermaine and Taverna, Federico and Queiroz, Karla CS and Dubois, Charlotte and Cantelmo, Anna Rita and Chen, Rongyuan and Loroch, Stefan and Timmerman, Evy and Caixeta, Vanessa and Bloch, Katarzyna and Conradi, Lena-Christin and Treps, Lucas and Staes, An and Gevaert, Kris and Tee, Andrew and Dewerchin, Mieke and Semenkovich, Clay F and Impens, Francis and Schilling, Birgit and Verdin, Eric and Swinnen, Johannes V and Meier, Jordan L and Kulkarni, Rhushikesh A and Sickmann, Albert and Ghesquière, Bart and Schoonjans, Luc and Li, Xuri and Mazzone, Massimiliano and Carmeliet, Peter}},
  issn         = {{1550-4131}},
  journal      = {{CELL METABOLISM}},
  keywords     = {{LYSINE MALONYLATION,CANCER-CELLS,TUMOR,ACETYLATION,METABOLISM,GROWTH,CARCINOMA,OVEREXPRESSION,STOICHIOMETRY,LIPOGENESIS}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{866--880}},
  title        = {{Impairment of angiogenesis by fatty acid synthase inhibition involves mTOR malonylation}},
  url          = {{http://dx.doi.org/10.1016/j.cmet.2018.07.019}},
  volume       = {{28}},
  year         = {{2018}},
}

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