期刊
EUROPEAN JOURNAL OF CANCER PREVENTION
卷 25, 期 1, 页码 54-64出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CEJ.0000000000000141
关键词
AMPK; carbohydrate restriction; chemoprevention; energy metabolism; liver cancer; melanoma; phytochemical; SIRT1
类别
资金
- Brain Korea 21 project at the Yonsei Medical College of Medicine [7-2007-0352]
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2013-31-0342]
Calorie restriction or a low-carbohydrate diet (LCD) can increase life span in normal cells while inhibiting carcinogenesis. Various phytochemicals also have calorie restriction-mimetic anticancer properties. We investigated whether an isocaloric carbohydrate-restriction diet and AMP-activated protein kinase (AMPK)-activating phytochemicals induce synergic tumor suppression. We used a mixture of AMPK-activating phytochemical extracts including curcumin, quercetin, catechins, and resveratrol. Survival analysis was carried out in a B16F10 melanoma model fed a control diet (62.14%kcal carbohydrate, 24.65%kcal protein and 13.2%kcal fat), a control diet with multiple phytochemicals (MP), LCD (16.5, 55.2, and 28.3%kcal, respectively), LCD with multiple phytochemicals (LCDmp), a moderate-carbohydrate diet (MCD, 31.9, 62.4, and 5.7%kcal, respectively), or MCD with phytochemicals (MCDmp). Compared with the control group, MP, LCD, or MCD intervention did not produce survival benefit, but LCDmp (22.80 +/- 1.58 vs. 28.00 +/- 1.64 days, P=0.040) and MCDmp (23.80 +/- 1.08 vs. 30.13 +/- 2.29 days, P=0.008) increased the median survival time significantly. Suppression of the IGF-1R/PI3K/Akt/mTOR signaling, activation of the AMPK/SIRT1/LKB1pathway, and NF-B suppression were the critical tumor-suppression mechanisms. In addition, SIRT1 suppressed proliferation of the B16F10 and A375SM cells under a low-glucose condition. Alterations in histone methylation within Pten and FoxO3a were observed after the MCDmp intervention. In the transgenic liver cancer model developed by hydrodynamic transfection of the HrasG12V and shp53, MCDmp and LCDmp interventions induced significant cancer-prevention effects. Microarray analysis showed that PPAR increased with decreased IL-6 and NF-B within the hepatocytes after an MCDmp intervention. In conclusion, an isocaloric carbohydrate-restriction diet and natural AMPK-activating agents induce synergistic anticancer effects. SIRT1 acts as a tumor suppressor under a low-glucose condition.
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