Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation

被引：231

作者：

Bruning, Ulrike ^{[1
,2
,3
,4
]}

Morales-Rodriguez, Francisco ^{[1
,3
,4
]}

Kalucka, Joanna ^{[1
,3
,4
]}

Goveia, Jermaine ^{[1
,3
,4
]}

Taverna, Federico ^{[1
,3
,4
]}

Queiroz, Karla C. S. ^{[1
,3
,4
]}

Dubois, Charlotte ^{[1
,3
,4
]}

Cantelmo, Anna Rita ^{[1
,3
,4
]}

Chen, Rongyuan ^{[2
]}

Loroch, Stefan ^{[5
]}

Timmerman, Evy ^{[6
,7
,8
]}

Caixeta, Vanessa ^{[5
]}

Bloch, Katarzyna ^{[9
]}

Conradi, Lena-Christin ^{[1
,3
,4
]}

Treps, Lucas ^{[1
,3
,4
]}

Staes, An ^{[6
,7
,8
]}

Gevaert, Kris ^{[6
,7
,8
]}

Tee, Andrew ^{[10
]}

Dewerchin, Mieke ^{[1
,3
,4
]}

Semenkovich, Clay F. ^{[11
]}

Impens, Francis ^{[6
,7
,8
]}

Schilling, Birgit ^{[12
]}

Verdin, Eric ^{[12
]}

Swinnen, Johannes V. ^{[9
]}

Meier, Jordan L. ^{[13
]}

Kulkarni, Rhushikesh A. ^{[13
]}

Sickmann, Albert ^{[5
]}

Ghesquiere, Bart ^{[14
,15
]}

Schoonjans, Luc ^{[1
,2
,3
,4
]}

Li, Xuri ^{[2
]}

Mazzone, Massimiliano ^{[16
,17
]}

Carmeliet, Peter ^{[1
,2
,3
,4
]}

机构：

[1] VIB, Lab Angiogenesis & Vasc Metab, VIB Ctr Canc Biol CCB, B-3000 Leuven, Belgium

[2] Sun Yat Sen Univ, State Key Lab Ophthalmol, Zhongshan Ophthalm Ctr, Guangzhou 510060, Guangdong, Peoples R China

[3] Katholieke Univ Leuven, Lab Angiogenesis & Vasc Metab, Dept Oncol, B-3000 Leuven, Belgium

[4] Katholieke Univ Leuven, Leuven Canc Inst LKI, B-3000 Leuven, Belgium

[5] ISAS, Leibniz Inst Analyt Wissensch, D-44227 Dortmund, Germany

[6] VIB Ctr Med Biotechnol, B-9000 Ghent, Belgium

[7] Univ Ghent, Dept Biochem, B-9000 Ghent, Belgium

[8] VIB Prote Expertise Ctr, B-9000 Ghent, Belgium

[9] Katholieke Univ Leuven, Lab Lipid Metab & Canc, Dept Oncol, B-3000 Leuven, Belgium

[10] Cardiff Univ, Cardiff CF14 4YS, S Glam, Wales

[11] Washington Univ, Div Endocrinol Metab & Lipid Res, St Louis, MO 63110 USA

[12] Buck Inst Res Aging, Novato, CA 94945 USA

[13] NCI, Frederick, MD 21702 USA

[14] Katholieke Univ Leuven, Metabol Core Facil, Dept Oncol, B-3000 Leuven, Belgium

[15] VIB, Metabol Core Facil, VIB Ctr Canc Biol CCB, B-3000 Leuven, Belgium

[16] VIB, Lab Tumor Inflammat & Angiogenesis, VIB Ctr Canc Biol CCB, B-3000 Leuven, Belgium

[17] Katholieke Univ Leuven, Lab Tumor Inflammat & Angiogenesis, Dept Oncol, B-3000 Leuven, Belgium

来源：

CELL METABOLISM | 2018年 / 28卷 / 06期

基金：

欧洲研究理事会; 中国国家自然科学基金;

关键词：

LYSINE MALONYLATION; CANCER-CELLS; TUMOR; ACETYLATION; METABOLISM; GROWTH; CARCINOMA; OVEREXPRESSION; STOICHIOMETRY; LIPOGENESIS;

D O I：

10.1016/j.cmet.2018.07.019

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：866 / +

页数：30

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