The G protein-coupled P2Y₆ receptor promotes colorectal cancer tumorigenesis by inhibiting apoptosis.

Colorectal tumors are immersed in an array of tumor-promoting factors including extracellular nucleotides such as uridine 5'‑diphosphate (UDP). UDP is the endogenous agonist of the G protein-coupled P2Y receptor (P2YR), which may contribute to the formation of a tumor-promoting microenvironment by coordinating resistance to apoptosis. Colorectal cancer (CRC) was chemically induced in P2ry6 knockout (P2ry6) mice using azoxymethane and dextran sulfate sodium challenges. Mice were euthanatized and their tumor load determined. Fixed tissues were stained for histological and immunohistochemistry analysis. Tumoroids were also prepared from CRC tumors resected from P2ry6 mice to determine the role of P2YR in resistance to apoptosis, whereas HT29 carcinoma cells were used to elucidate the signaling mechanism involved in P2YR anti-apoptotic effect. P2ry6 mice developed a reduced number of colorectal tumors with apparent tumors having smaller volumes. Overall dysplastic score was significantly lower in P2ry6 animals. Stimulation of P2YR with the selective agonist MRS2693 protected HT-29 cells from TNFα-induced apoptosis. This protective effect was mediated by the stabilizing phosphorylation of the X-linked inhibitor of apoptosis protein (XIAP) by AKT. Using CRC-derived tumoroids, P2YR activation was found to contribute to chemoresistance since addition of the P2YR agonist MRS2693 significantly prevented the cytotoxic effect of 5-fluorouracil. The present study shows that sustained activation of P2YR may contribute to intestinal tumorigenesis by blocking the apoptotic process and by contributing to chemoresistance, a substantial concern in the treatment of patients with CRC. These results suggest that P2YR may represent a prime target for reducing colorectal carcinogenesis.