title: Prevention of Dietary-Fat-Fueled Ketogenesis Attenuates BRAF V600E Tumor Growth.
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.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Xia
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Ruiting
authors.initials: R
authors.lastname: Lin
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Lingtao
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Hee-Bum
authors.initials: HB
authors.lastname: Kang
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Yaozhu
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Shuangping
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Qian
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Qian
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Evmorfia
authors.initials: E
authors.lastname: Konstantakou
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Baotong
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Jin-Tang
authors.initials: JT
authors.lastname: Dong
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Young Rock
authors.initials: YR
authors.lastname: Chung
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.affiliation: Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Ragini R
authors.initials: RR
authors.lastname: Kudchadkar
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Lawson
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Hanna J
authors.initials: HJ
authors.lastname: Khoury
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Boise
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lee
authors.affiliation: Department of Dermatology, Emory University, Atlanta, GA 30322, USA; Atlanta Veterans Administration Medical Center, Atlanta, GA 30322, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Pollack
authors.affiliation: Department of Dermatology, Emory University, Atlanta, GA 30322, USA; Atlanta Veterans Administration Medical Center, Atlanta, GA 30322, USA.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
authors.affiliation: Department of Radiation Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA. Electronic address: jfan3@emory.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Fan
authors.affiliation: Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address: qlei@fudan.edu.cn.
authors.forename: Qun-Ying
authors.initials: QY
authors.lastname: Lei
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA. Electronic address: jchen@emory.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology; D000090:Acetoacetates / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004041:Dietary Fats / Q000009:adverse effects*; D005260:Female; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007657:Ketone Bodies / Q000378:metabolism*; D008545:Melanoma / Q000097:blood / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011753:Pyrones / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000090:Acetoacetates; D004041:Dietary Fats; D000960:Hypolipidemic Agents; D007657:Ketone Bodies; D011753:Pyrones; C027493:dehydroacetic acid; C016635:acetoacetic acid; D048493:Proto-Oncogene Proteins B-raf; D020155:3-Hydroxybutyric Acid
keywords: BRAF V600E; acetoacetate; cancer metabolism; cancer prevention; cancer risk; cancer therapy; dehydroacetic acid; dietary fat; ketogenesis; precision diet