Xia Siyuan, Lin Ruiting, Jin Lingtao, Zhao Liang, Kang Hee-Bum, Pan Yaozhu, Liu Shuangping, Qian Guoqing, Qian Zhiyu, Konstantakou Evmorfia, Zhang Baotong, Dong Jin-Tang, Chung Young Rock, Abdel-Wahab Omar, Merghoub Taha, Zhou Lu, Kudchadkar Ragini R, Lawson David H, Khoury Hanna J, Khuri Fadlo R, Boise Lawrence H, Lonial Sagar, Lee Benjamin H, Pollack Brian P, Arbiser Jack L, Fan Jun, Lei Qun-Ying, Chen Jing
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Cell Metab. 2017 Feb 7;25(2):358-373. doi: 10.1016/j.cmet.2016.12.010. Epub 2017 Jan 12.
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.
包括饮食在内的生活方式因素在癌症患者的生存中起着重要作用。然而，饮食与人类癌症中特定致癌突变之间致病联系的分子机制仍不清楚。我们最近报道，酮体乙酰乙酸盐在人类癌症中选择性增强BRAF V600E突变依赖性的MEK1激活。在此我们表明，高脂肪生酮饮食会增加血清乙酰乙酸盐水平，导致在异种移植小鼠中表达BRAF V600E的人黑色素瘤细胞的肿瘤生长潜力增强。用降血脂药物降低循环中的乙酰乙酸盐水平，或用乙酰乙酸盐的抑制性类似物脱氢乙酸拮抗乙酰乙酸盐与BRAF V600E的结合，可减弱BRAF V600E肿瘤的生长。这些发现揭示了饮食脂肪在表达BRAF V600E的黑色素瘤中致病作用的信号基础，为基于个体特定致癌突变谱来预防或延缓肿瘤进展的概念化“精准饮食”设计提供了见解。
