Dynamic Effects of Ketogenic Diet on Autophagy and Cell Cycle in a Mouse Model of CT26+ Colon Cancer
Dynamic Effects of Ketogenic Diet on Autophagy and Cell Cycle in a Mouse Model of CT26+ Colon Cancer
Junrong Yang1, Ning Zhang1*, Muhammad Akram Khan2, Qingpeng Wang1*, Zhengping Wang1*, Quiqin Liu3, Lanjie Li3, Jun Han1, Abdul Asim Farooq4, Aayesha Riaz5 and Ruiyan Zhang1
ABSTRACT
Colon cancer often has problems of recurrence and chemotherapy resistance in the late stage. Metabolic reprogramming is one of the characteristics of colon tumors and contributes to autophagy and cell cycle progression of tumors. A ketogenic diet (KD) is a high-fat, adequate-protein, and low-carbohydrate diet with documented anti-tumor effects. However, the mechanism of KD inhibiting colon cancer remains unclear. In this study, we investigated the molecular mechanism underlying the effects of KD on cell cycle and autophagy in colon tumor-bearing mice. Our results showed that compared with the SD group, KD treatment upregulated the expressions of autophagy-related proteins LC3-II and Beclin-1 while downregulated the expression of p62 protein in CT26+ tumor-bearing mice. In parallel, the expressions of CDK4-Cyclin D1 and CDK2-Cyclin E proteins were decreased, while the expression of p21 and p16 proteins increased in KD group. The data analysis suggested that KD promoted autophagy and blocked the tumor cell cycle in the G1/S phase. In addition, the western blot showed that KD significantly downregulated the expressions of PI3K, p-Akt, p-mTOR, HDAC3, p-JAK2 and p-STAT3 proteins. In vitro results (RGFP966, an HDAC3 inhibitor, and NSC74859, a STAT3 inhibitor) also supported those of the in vivo findings. Overall, the current study demonstrated that KD induced autophagy and G1/S phase cell cycle arrest in tumors by inhibiting the activation of the PI3K/Akt/mTOR, STAT3/HDAC3 and JAK2/STAT3 signaling pathways. Together, we can conclude that KD prevents colon cancer progression by regulating autophagy and cell cycle arrest of tumor cells.
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