Polyphenols as Modulators of the BMP Signaling Pathway to Counter Phenotypic Transformation of Colonocytes

The intestinal bone morphogenetic protein (BMP) pathway counteracts the Wnt pathway, which is overactivated in 90% of colorectal cancers (CRC) due to mutations in the adenomatous polyposis coli (APC) gene. Our study aimed to identify a polyphenol that acts on the colonic BMP pathway and to evaluate its ability to mitigate the harmful effects of 4-hydroxynonenal (HNE), a dietary genotoxic molecule, on normal colonocytes. We first evaluated the effect of 10 polyphenols on the expression of BMP pathway actors using a normal mouse colonocyte and fibroblast culture model. Apigenin (Apig) and resveratrol (Res) increased the production of BMP4 ligand and reduced expression of the Gremlin1 (Grem1) antagonist in fibroblasts. Apig also enhanced the expression of the bone morphogenetic protein receptor type 2 (Bmpr2) in fibroblasts and that of the Smad1 effector in colonocytes. Finally, Apig inhibited the phenotypic transformation of colonocytes induced by HNE through a mechanism that involved the BMP pathway in both fibroblasts and colonocytes. Our findings suggest that targeting the colonic BMP signaling pathway through dietary factors could contribute to the prevention of CRC. Apig-rich foods or supplements may play a role in this preventive nutrition, although further in vivo experiments are needed to confirm this potential.