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Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation

  1. Author:
    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
    Kulkarni, Rhushikesh A
    Sickmann, Albert
    Ghesquière, Bart
    Schoonjans, Luc
    Li, Xuri
    Mazzone, Massimiliano
    Carmeliet, Peter

  2. Author Address

    Laboratory of Angiogenesis and Vascular Metabolism, VIB Center for Cancer Biology (CCB), VIB, 3000 Leuven, Belgium; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, P.R. China; Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, 3000 Leuven, Belgium., Laboratory of Angiogenesis and Vascular Metabolism, VIB Center for Cancer Biology (CCB), VIB, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, 3000 Leuven, Belgium., State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, P.R. China., Leibniz Institut f 252;r analytische Wissenschaften, ISAS, 44227 Dortmund, Germany., VIB Center for Medical Biotechnology, 9000 Ghent, Belgium; Department of Biochemistry, Ghent University, 9000 Ghent, Belgium; VIB Proteomics Expertise Center, 9000 Ghent, Belgium., Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven, 3000 Leuven, Belgium., Cardiff University, Cardiff CF14 4YS, UK., Division of Endocrinology, Metabolism & Lipid Research, Washington University, St. Louis, MO 63110, USA., Buck Institute for Research on Aging, Novato, CA 94945, USA., National Cancer Institute, Frederick, MD 21702, USA., Metabolomics Core Facility, Department of Oncology, KU Leuven, 3000 Leuven, Belgium; Metabolomics Core Facility, VIB Center for Cancer Biology (CCB), VIB, 3000 Leuven, Belgium., State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, P.R. China. Electronic address: lixr6@mail.sysu.edu.cn., Laboratory of Tumor Inflammation and Angiogenesis, VIB Center for Cancer Biology (CCB), VIB, 3000 Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, 3000 Leuven, Belgium., Laboratory of Angiogenesis and Vascular Metabolism, VIB Center for Cancer Biology (CCB), VIB, 3000 Leuven, Belgium; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, P.R. China; Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, 3000 Leuven, Belgium. Electronic address: peter.carmeliet@kuleuven.vib.be.,
    1. Year: 2018
    2. Date: Dec 4
    3. Epub Date: 2018 08 21
  2. Journal: Cell Metabolism
    1. 28
    2. 6
    3. Pages: 866-880.e15
  4. Type of Article: Article
  5. ISSN: 1550-4131
  1. 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. Copyright © 2018 Elsevier Inc. All rights reserved.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.cmet.2018.07.019
  3. PMID: 30146486
  4. View record in Web of Science®
  5. WOS: 000452451000010
  6. PII : S1550-4131(18)30462-5

Library Notes

  1. Fiscal Year: FY2017-2018
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