Molecular Insights of Resveratrol on Preventing Colorectal Cancer driven by mutant BRAF

Cancer is a leading cause of death worldwide. In the UK every two minutes someone is diagnosed with cancer. Colorectal cancer (CRC) is the fourth most common cancer behind breast, prostate and lung cancer. About 10% of CRC patients have tumours with a mutation in BRAF and it is found to be mutated in 15% of all known human cancers. BRAF is a central kinase of the RAS/RAF/MEK pathway involved in cell growth and proliferation and BRAF V600E mutation is the most common type of mutations. BRAF mutant tumours have shown poor survival rates and drug resistance in CRC. Resveratrol (Res) is a phytoalexin produced by plants which possesses high antioxidative potential. It is a promising anticancer agent and has been investigated for the prevention and treatment of a variety of cancers, including CRC. Previous work in our group using a mouse model of BRAF- driven CRC carcinogenesis had showed that Res can dramatically extend survival, when mice were maintained on a high fat diet (HFD). This study aims to elucidate the mechanism of action that contributes to this protective effect of Res. The initial focus was exploring effects on ketogenesis and fat metabolism and the integrity of the intestinal barrier. Gut barrier integrity analysis revealed that there was a compromised gut barrier integrity in the 6 weeks mutant BRAF mice compared to wild type (WT) mice which was analysed by FITC dextran experiment. The cumulative distribution of number of cells/crypt analysis had shown that BRAF mutation, caused significant reduction of cell number in 3 days mutant BRAF mice on HFD. Whereas, in 6 weeks mutant BRAF mice on HFD, only high dose of Res had shown a significant decrease in cell number. Immunohistochemical staining of 8-oxo-dG protein showed that there was oxidative DNA damage in the intestinal villi of the 6 weeks mutant BRAF mice and the lower dose of Res had shown a significant reduction in the DNA damage on mutant BRAF mice, on HFD. The high dose of Res (143 ppm) had also shown a beneficial effect on HFD induced dysplasia which was evident in the pathological report of diet switching study and also decreased the lipid droplets formation in 6 weeks study. These results had provided the valuable insight of Res, to protect against the development of BRAF V600E driven CRC and further studies are required to explore the antiproliferative effects of Res and to understand the harmful effects of HFD on BRAF V600E mutagenesis in humans thus preventing CRC tumorigenesis.