P2Y6 receptor activation promotes the migration, invasion and glycogen accumulation of colorectal cancer through AKT/mTOR signaling.

Recent studies have shown that G protein-coupled P2Y6 receptor (P2Y6R) can play a promoting or inhibitory role in some tumors, but the functional effect of P2Y6R on the migration and invasion of colorectal cancer (CRC) is still poorly understood. Therefore, this study comprehensively investigated whether the P2Y6R plays a promoting or inhibiting role in the migration and invasion of CRC. Public databases were used to investigate the intrinsic association between P2Y6R and CRC tissue. Functional experiments was used to investigate the effects of P2Y6R activation or inhibition on CRC migration, invasion, cytoskeleton and glycogen accumulation. The results showed that high expression of P2Y6R was negatively correlated with overall survival and prognosis of CRC patients. The P2Y6R agonist (UDP) opened the function of the pore on the cell membrane and increased the influx of calcium ions, while antagonistic to its activation could produce a significant inhibitory effect. UDP promoted the migration and invasion capabilities of CRC cells, enhanced the fibrin stress capabilities of the cytoskeleton, and promoted the glycogen accumulation capabilities of cells. However, the P2Y6R antagonist MRS2578 or MRS4853 significantly inhibited these changes induced by UDP. Moreover, the P2Y6R had a clear correlation with AKT/mTOR in patients with CRC tissues. UDP increased the protein expression levels of p-AKT and p-mTOR in CRC cells, while P2Y6R antagonists decreased the protein expression levels of p-AKT and p-mTOR by inhibiting P2Y6R activity. In addition, based on P2Y6R activation, the application of AKT/mTOR pathway inhibitor BGT226 inhibited UDP-induced migration, invasion, cytoskeleton and glycogen accumulation of CRC cells. Combined intervention of P2Y6R antagonists and BGT226 produced additive inhibitory pharmacological effects. These data reveal that high expression of P2Y6R contributes to poor overall survival outcomes in patients with CRC. Activation of P2Y6R promotes the migration, invasion and glycogen accumulation of CRC cells, and the mechanism may be related to the AKT/mTOR pathway. This also reveals that the P2Y6R can be used as another important target for the prevention and treatment of CRC.