Resveratrol’s effects on a BRAF mutant mouse model of colorectal carcinogenesis


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Grandezza Aburido1,Hong Cai1,Raj Singh1,Don Jones1,Rob Britton1,Karen Brown1
1University of Leicester

Abstract

Background

Prevention of colorectal cancer (CRC), the second most common cause of cancer death in the UK, is feasible. However, safer therapeutic options are needed to improve preventive efficacy across various CRC subtypes. Moreover, few studies have attempted to identify/develop therapies to prevent the BRAFV600E mutant (BRAF+) subtype which leads to a poor prognosis. Interestingly we have found that resveratrol, a natural compound with anti-cancer properties, significantly prolongs the survival of BRAF+ mice. This increased survival, however, is observed only when the mice are given a high-fat diet (HFD) and not a normal-fat diet (NFD) (unpublished). The aim of this study was to investigate, at protein level, the effects of resveratrol in this HFD-fed mouse model and potential reasons for the survival increase.

Method

Mouse intestine sections and plasma from 3-day and 6-week resveratrol intervention studies were analysed via proteomic techniques, and protein expression differences established bioinformatically. Two resveratrol doses were studied, 0.7ppm and 143ppm – 143ppm being equivalent to 1g in humans.

Results

Protein changes differ at 3 days and at 6 weeks but generally, a BRAF+ along with a HFD led to expression changes of proteins with potentially pro-cancer activities. Many of these changes were ‘reversed’ by both doses of resveratrol, but the higher dose of resveratrol was shown to be more effective. Bioinformatics disclosed the pro-cancer protein functions/processes reversed by resveratrol to include processes such as cell division/differentiation, neural development, and calcium signalling. Potential biomarkers of resveratrol's efficacy were also identified from the plasma, such as SPTLC2 and ATP2B2.

Conclusion

From this study, insight on the largely pleiotropic effects of resveratrol in this BRAF mutant model along with a HFD was identified at protein level, and evidence of how resveratrol prolongs survival of these mice has also been obtained. Thus, resveratrol’s potential chemopreventive properties in this particular CRC subtype has been elucidated.