Activation of the P2Y1 receptor induces apoptosis and inhibits proliferation of prostate cancer cells

G protein-coupled receptors, the largest cell surface receptor family, have emerged as critical players in cell death and survival. High gene expression level of the Gq-coupled P2Y1 nucleotide receptor in PC-3 prostate cancer cells was demonstrated using real-time quantitative PCR and confirmed by Western blotting and confocal laser scanning microscopy. A selective P2Y1 receptor agonist, the ADP analogue MRS2365, concentration-dependently induced intracellular calcium mobilization (EC50 5.28 nM), which was diminished by P2Y1 receptor-selective antagonist MRS2500. P2Y1 receptor activation by MRS2365 induced apoptosis in assays of Caspase-3, LDH release, and annexin-V staining. The pro-apoptotic effect of MRS2365 was blocked by MRS2500, P2Y1 siRNA, and an inhibitor of the MAP kinase pathway PD98059. MRS2365 significantly inhibited the proliferation of PC-3 cells, examined using a MTT assay. Thus, activation of the P2Y1 receptor induced cell death and inhibited growth of human prostatic carcinoma PC-3 cells. Activation of the P2Y1 receptor should be a novel and promising therapeutic strategy for prostate cancer.

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