The blockage of downstream P2Y 2 receptor signaling inhibits the prostate cancer cell adhesion to endothelial cells.

Aims: Prostate cancer is the second most frequently malignancy in men worldwide. Most deaths are caused by metastasis, and tumor cell dissemination involves the interaction with endothelial cells. However, the endothelial cell signaling involved in such interaction is not entirely understood. The tumor microenvironment contains extracellular ATP, an endogenous agonist of the purinergic P2Y ₂ receptor (P2Y ₂ R). P2Y ₂ R signaling changes endothelial cell phenotype, which may be relevant to cancer pathophysiology. Therefore, we hypothesized that P2Y ₂ R activation could favor the metastatic prostate cancer cells adhesion to endothelial cells.
Main Methods: For adhesion assays, confluent endothelial cells EA.hy926 were treated with P2Y ₂ R agonists before adding and imaging stained DU-145 cells. Alternatively, fluorescent probes and antibodies were used to determine intracellular endothelial Ca ²⁺ , nitric oxide (NO), and flow cytometry assays.
Key Findings: Endothelial P2Y ₂ R activation with ATP, UTP, or the selective agonist 2-thio-UTP increased DU-145 cell adhesion to EA.hy926 cells. This effect required endothelial cell Ca ²⁺ mobilization and relied on the endothelial expression of VCAM-1 and ICAM-1. Conversely, inhibiting this proadhesive endothelial phenotype could impair DU-145 cell adhesion. To evaluate this, we chose atorvastatin based on its notable improvement of endothelial cell dysfunction. Atorvastatin blocked UTP-induced DU-145 cell adhesion to endothelial cell monolayer in a NO-dependent manner, unveiling a P2Y ₂ R and NO signaling crosstalk.
Significance: Endothelial P2Y ₂ R signaling contributes to the adhesion of metastatic prostate cancer cells suggesting that the downstream signaling blockade by statins could be a putative mechanism to reduce prostate cancer metastasis.
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