Role and recent progress of P2Y12 receptor in cancer development

Abstract

P2Y12 receptor (P2Y12R) is an adenosine-activated G protein-coupled receptor (GPCR) that plays a central role in platelet function, hemostasis, and thrombosis. P2Y12R activation can promote platelet aggregation and adhesion to cancer cells, promote tumor angiogenesis, and affect the tumor immune microenvironment (TIME) and tumor drug resistance, which is conducive to the progression of cancers. Meanwhile, P2Y12R inhibitors can inhibit this effect, suggesting that P2Y12R may be a potential therapeutic target for cancer. P2Y12R is involved in cancer development and metastasis, while P2Y12R inhibitors are effective in inhibiting cancer. However, a new study suggests that long-term use of P2Y12R inhibitors may increase the risk of cancer and the mechanism remains to be explored. In this paper, we reviewed the structural and functional characteristics of P2Y12R and its role in cancer. We explored the role of P2Y12R inhibitors in different tumors and the latest advances by summarizing the basic and clinical studies on the effects of P2Y12R inhibitors on tumors.

Keywords: P2Y12R; P2Y12R inhibitors; Platelets; Tumor; Tumor microenvironment.

Fig. 1

Summary of the mechanism of P2Y12R in platelets. After P2Y12R binds to ADP, the coupled Gi protein dissociates into G α i2 and G β γ. Phosphorylation of pi3k-dependent protein kinase B (PKB)/Akt and activation of Rap 1b are induced by recruitment of β γ subunit to activate inositol phosphoinositide-3-kinase (PI3K) and positively regulate the activation of integrin GPIIb/IIIa. This method helps to stabilize platelet aggregation and amplifies the platelet aggregation caused by the coupling of P2Y1R with Gi after being activated by ADP and the platelet secretion induced by the interaction between other strong agonists and platelet receptors. Additionally, this can directly promote platelet secretion, promote the secretion of TXA2, and contribute to thrombus stability, and it promotes platelet degranulation. Among them, platelet dense particles store high ADP concentrations, which promotes the release of dense particles and amplifies most platelet reactions in a positive feedback manner. Alpha granules contain many active substances, including pro-inflammatory or anti-inflammatory molecules, chemokines, adhesion molecules, and growth factors. The typical way to promote the release of α-granules is the upregulation of P-selectin. P2Y12R mediates the inhibition of adenylate cyclase by interacting with α subunits, and mediating the production of cyclic AMP (cAMP) through coupling with G α i2, resulting in impaired activation of protein kinase A (PKA), followed by inhibition of vasodilator-stimulated phosphorylated protein (VASP), thus inhibiting platelet secretion or adhesion events. However, inhibition of prostaglandin I2 (prostacyclin) and adenosine may contribute to platelet aggregation by increasing the inhibition of platelet aggregation induced by platelet cAMP. Symbol legend: arrow line, activation; truncation line, suppression; line ending with (+), enlarged; horizontal arc arrow, metabolic transformation