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Cell Metab. 2017 Feb 7;25(2):358-373. doi: 10.1016/j.cmet.2016.12.010. Epub 2017 Jan 12.

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

Author information

1
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
2
Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
4
Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
5
Department of Dermatology, Emory University, Atlanta, GA 30322, USA; Atlanta Veterans Administration Medical Center, Atlanta, GA 30322, USA.
6
Department of Radiation Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA. Electronic address: jfan3@emory.edu.
7
Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address: qlei@fudan.edu.cn.
8
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.

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.

KEYWORDS:

BRAF V600E; acetoacetate; cancer metabolism; cancer prevention; cancer risk; cancer therapy; dehydroacetic acid; dietary fat; ketogenesis; precision diet

PMID:
28089569
PMCID:
PMC5299059
DOI:
10.1016/j.cmet.2016.12.010
[Indexed for MEDLINE]
Free PMC Article

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