Prevention of Dietary-Fat-Fueled Ketogenesis Attenuates BRAF V600E Tumor Growth

• Type of Material: Article
• Authors: Siyuan Xia, Emory University; Ruiting Lin, Emory University; Lingtao Jin, Emory University; Liang Zhao, Emory University; Hee-Bum Kang, Emory University; Yaozhu Pan, Emory University; Shuangping Liu, Emory University; Guoging Qian, Emory University; Zhiyu Qian, Emory University; Evmorfia Konstantakou, Emory University; Baotong Zhang, Emory University; Jin-Tang Dong, Emory University; Young Rock Chung, Memorial Sloan-Kettering Cancer Center; Omar Abdel-Wahab, Memorial Sloan-Kettering Cancer Center; Taha Merghoub, Memorial Sloan-Kettering Cancer Center; Lu Zhou, Fudan University; Ragini R. Kudchadkar, Emory University; David H Lawson, Emory University; H Jean Khoury, Emory University; Fadlo Khuri, Emory University; Lawrence Boise, Emory University; Sagar Lonial, Emory University; Benjamin H. Lee, Novartis Institutes for BioMedical Research; Brian P Pollack, Emory University; Jack Arbiser, Emory University; Jun Fan, Emory University; Qun-Ying Lei, Fudan University; Jing Chen, Emory University
• Language: English
• Date: 2017-02-07
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cmet.2016.12.010
• Title of Journal or Parent Work: Cell Metabolism
• ISSN: 1550-4131
• Volume: 25
• Issue: 2
• Start Page: 358
• End Page: 373
• Grant/Funding Information: This work was supported in part by NIH grants CA140515, CA183594, CA174786 (J.C.), and AR47901 (J.L.A.), and also by the Joel A. Katz Music Medicine Fund supported by the T.J. Martell Foundation and the Winship Cancer Institute (J.C. and R.L.), the Jamie Rabinowitch Davis Foundation (J.L.A.), the Charles Harris Run For Leukemia (H.J.K.), the Melanoma Research Foundation, and the Winship Cancer Institute melanoma and skin cancer fund (B.P.P.).
• Keywords: Science & Technology; Cell Biology; KETONE-BODY METABOLISM; CANCER; WEIGHT; OBESITY; EXERCISE; THERAPY; Endocrinology & Metabolism; Life Sciences & Biomedicine; MELANOMA RISK; MALIGNANT-MELANOMA; METAANALYSIS; HYPERCHOLESTEROLEMIA
• Research Categories: Health Sciences, Oncology

Abstract

Lifestyle factors, including diet, play an important role in the survival of cancer patients. However, the molecular mechanisms underlying pathogenic links between diet and particular oncogenic mutations in human cancers remain unclear. We recently reported that the ketone body acetoacetate selectively enhances BRAF V600E mutant-dependent MEK1 activation in human cancers. Here we show that a high-fat ketogenic diet increased serum levels of acetoacetate, leading to enhanced tumor growth potential of BRAF V600E-expressing human melanoma cells in xenograft mice. Treatment with hypolipidemic agents to lower circulating acetoacetate levels or an inhibitory homolog of acetoacetate, dehydroacetic acid, to antagonize acetoacetate-BRAF V600E binding attenuated BRAF V600E tumor growth. These findings reveal a signaling basis underlying a pathogenic role of dietary fat in BRAF V600E-expressing melanoma, providing insights into the design of conceptualized “precision diets” that may prevent or delay tumor progression based on an individual's specific oncogenic mutation profile.