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

Abstract

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.

Comprehensive analysis of ferritin subunits expression and positive correlations with tumor-associated macrophages and T regulatory cells infiltration in most solid tumors

“…Moreover, our analyses revealed positive associations between FTL and FTH1 expressions and infiltration of both cell types in most cancers. Mounting evidence suggests that TAMs exhibit high plasticity and can switch between the anti-tumoral M1 subtype and the pro-tumoral M2 subtype, the latter of which is most abundant in solid tumors [ 41 , 42 ]. Ricolleau reported that FTL is mainly stored in M2-like TAMs in node-negative breast cancer [ 43 ].…”

Precision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers

“…Furthermore, βhB inhibits the NFκB component of the pathway by binding GPR109A receptor [96,97], which the Montagne group found was sufficient to protect the BBB in ApoE4 mice [21]. Additionally, a ketogenic diet in mice was recently shown to inhibit HDAC, NFκB, and MMP9 expression [98].…”

Ketogenic Diet in Cancer Prevention and Therapy: Molecular Targets and Therapeutic Opportunities

“…Additionally, MMP-9 comprises the gelatinase sub-family of MMPs and is primarily produced by inflammatory cells and from the stromal cells surrounding a tumor or by the cancer cells themselves [146]. The use of ketogenic diet, in combination with other conventional cancer therapy, is expected to provide a noticeable reduction in the expression of MMP-9 in different types of cancer [142,147].…”