P2Y6 receptor inhibition arrests tumor cell progression in a mouse lymphoma model

Extracellular ATP (eATP) is a major component of the tumor microenvironment which has been shown to play an important role in inflammation and cancer. Previously, we have shown that eATP, through P2Y12 receptors, increased the levels of the pro-inflammatory enzyme cyclooxygenase 2 (COX-2) in tumor cells, which in turn imparted metastatic property to cancer cells. In a mouse model of lymphoma, we further showed that both the P2Y12 receptor-specific antagonist, AR-C 69931, and the P2Y6 receptor-specific antagonist, MRS 2578, significantly arrested tumor progression. In the case of tumor-bearing mice treated with AR-C 69931, a strong reduction in COX-2 expression was observed which in turn reduced metastasis. However, COX-2 expression was not altered in mice treated with MRS 2578. In this paper, we report that inhibition of the P2Y6 receptor acts through modulation of cell cycle proteins leading to cell cycle arrest. Our results show that blocking of P2Y6 receptors is a therapeutic alternative to arrest tumor growth and metastasis.