A proteomics-based investigation into the effects of Resveratrol in a high-fat diet fed murine model of Braf mutant colorectal cancer

Resveratrol (RSV) has been widely investigated for its range of biological benefits, such as its proposed chemopreventive properties – including in colorectal cancers (CRCs). CRCs are often initiated and progressed via gene mutations, such as the BrafV600E mutation (Braf+).

This Braf+ subtype accounts for around 10% of CRC cases, with poor prognosis and high rates of treatment resistance. Previously, RSV has been demonstrated to significantly increase the survival of Braf+ mice, but only when maintained on a high-fat diet (HFD). Therefore, the purpose of this study was to identify the mechanisms behind this survival increase, as well as to recognise RSV’S potential chemopreventive properties in an early Braf+ setting.

For this, the effects of two RSV doses (0.7ppm/143ppm) at 3 days and at 6 weeks were explored. Mass spectrometry-based proteomics techniques were employed to determine protein expression changes, particularly those caused by  the Braf+/HFD combination (COMB). In tissue, the majority of 143ppm RSV’s effects in a COMB setting was associated with CRC/cancer-related changes, whilst most 0.7ppm RSV-induced changes were not. In 6-week plasma, 143ppm RSV was able to reverse unfavourable COMB-induced changes in the complement and coagulation cascade (CCC). This suggests a plasma component behind the aforementioned survival effect, via improved protection through CCC changes. Additionally, 143ppm RSV led to the reduction in number and size of lipid droplets in tissue.

As lipids are an alternative source of fuel for tumourigenesis, this, with the CCC changes, potentially provides evidence of early preventive/protective activity.

A lower RSV dose over a longer period of time may be sufficient in exerting beneficial activity in tissue. Dosing/intervention route should be re-considered for future intervention studies, as 0.7ppm may be sufficient. Future studies that are larger and longer should be conducted to confirm these observations and discover the true potential of RSV for Braf+ CRCs.