Propionate suppresses colitis-associated colorectal cancer in mice by Or51e2

Dietary fiber intake is associated with a reduced risk of colorectal cancer (CRC), partly through the microbial fermentation of fiber into short-chain fatty acids (SCFAs). Among these, propionate binds to olfactory receptor 51E2 (Or51e2), which is ectopically expressed in the colon, but its role in CRC remains unclear. In this study, we evaluated Or51e2 expression in murine CT26 CRC cells and mouse colon tissues. Intracellular cAMP levels and CRE-luciferase activity were measured in CT26 and Or51e2-transfected Hana3A cells. The effects of propionate on proliferation, apoptosis, and MEK/ERK signaling were examined in CT26 cells. In vivo, a colitis-associated CRC model was established in wild-type (WT) and Or51e2-knockout (Or51e2 KO) mice using azoxymethane and dextran sulfate sodium (AOM/DSS). Propionate was administered intraperitoneally, and tumor burden, colon length, polyp number, histological changes, and MEK/ERK phosphorylation were assessed. Or51e2 expression was higher than other SCFA receptors in both CT26 cells and mouse colon tissues. Propionate treatment increased intracellular cAMP, activated CRE-luciferase, inhibited cell proliferation, induced apoptosis, and suppressed MEK/ERK phosphorylation in an Or51e2-dependent manner. In vivo, propionate reduced tumor growth, polyp formation, and MEK/ERK activation in WT mice, but not in Or51e2 KO mice. These findings suggest that Or51e2 mediates the anti-tumor effects of propionate through modulation of cAMP and MEK/ERK signaling, supporting its potential as a therapeutic strategy for CRC treatment.