Prevention of Dietary-Fat-Fueled Ketogenesis Attenuates BRAF V600E Tumor Growth
| Autor: | Lawrence H. Boise, Guoqing Qian, Brian Pollack, Lingtao Jin, Siyuan Xia, Taha Merghoub, Ragini R. Kudchadkar, Shuangping Liu, Jack L. Arbiser, Hanna Jean Khoury, Fadlo R. Khuri, Liang Zhao, Hee-Bum Kang, Jun Fan, Young Rock Chung, Omar Abdel-Wahab, Qun-Ying Lei, David H. Lawson, Jin-Tang Dong, Lu Zhou, Jing Chen, Baotong Zhang, Benjamin H. Lee, Zhiyu Qian, Evmorfia Konstantakou, Ruiting Lin, Yaozhu Pan, Sagar Lonial |
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| Rok vydání: | 2017 |
| Předmět: |
Proto-Oncogene Proteins B-raf
0301 basic medicine medicine.medical_specialty Physiology medicine.medical_treatment Mice Nude Ketone Bodies Biology Article Acetoacetates Mice 03 medical and health sciences 0302 clinical medicine Internal medicine Ketogenesis medicine Animals Humans Melanoma neoplasms Molecular Biology Cell Proliferation Hypolipidemic Agents Cancer prevention 3-Hydroxybutyric Acid Cancer Cell Biology medicine.disease Dietary Fats Xenograft Model Antitumor Assays 030104 developmental biology Endocrinology Pyrones Tumor progression 030220 oncology & carcinogenesis Mutation Cancer research Ketone bodies Female Injections Intraperitoneal V600E Ketogenic diet |
| Zdroj: | Cell Metabolism. 25:358-373 |
| ISSN: | 1550-4131 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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