Ketogenic Diet Elicits Antitumor Properties through Inducing Oxidative Stress, Inhibiting MMP‑9 Expression, and Rebalancing M1/M2 Tumor-Associated Macrophage Phenotype in a Mouse Model of Colon Cancer

• Published in: Journal of agricultural and food chemistry 2020-10, Vol.68 (40), p.11182-11196
• Main Authors: Zhang, Ning, Liu, Chunhong, Jin, Li, Zhang, Ruiyan, Wang, Ting, Wang, Qingpeng, Chen, Jingchao, Yang, Fang, Siebert, Hans-Christian, Zheng, Xuexing
• Format: Article
• Language: English
• Subjects: Animals; Bioactive Constituents, Metabolites, and Functions; Cell Line, Tumor; Colonic Neoplasms - diet therapy; Colonic Neoplasms - genetics; Colonic Neoplasms - immunology; Diet, Ketogenic; Disease Models, Animal; Humans; Male; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - immunology; Mice; Mice, Inbred BALB C; NF-kappa B - genetics; NF-kappa B - immunology; Oxidative Stress; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - immunology; Tumor-Associated Macrophages - immunology
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/acs.jafc.0c04041

Many advanced cancers are characterized by metabolic disorders. A dietary therapeutic strategy was proposed to inhibit tumor growth through administration of low-carbohydrate, average-protein, and high-fat diet, which is also known as ketogenic diet (KD). In vivo antitumor efficacy of KD on transplanted CT26+ tumor cells in BALB/c mice was investigated. The results showed that the KD group had significantly higher blood β-hydroxybutyrate and lower blood glucose levels when compared with the normal diet group. Meanwhile, KD increased intratumor oxidative stress, and TUNEL staining showed KD-induced apoptosis against tumor cells. Interestingly, the distribution of CD16/32+ and iNOS+ M1 tumor-associated macrophages (TAMs) increased in the KD-treated group, with concomitantly less arginase-1+ M2 TAMs. Moreover, KD treatment downregulated the protein expression of matrix metalloproteinase-9 in CT26+ tumor-bearing mice. Western blot analysis demonstrated that the expression levels of HDAC3/PKM2/NF-κB 65/p-Stat3 proteins were reduced in the KD-treated group. Taken together, our results indicated that KD can prevent the progression of colon tumor via inducing intratumor oxidative stress, inhibiting the expression of the MMP-9, and enhancing M2 to M1 TAM polarization. A novel potential mechanism was identified that KD can prevent the progression of colon cancer by regulating the expression of HDAC3/PKM2/NF-κB65/p-Stat3 axis.