Abstract 4597: The G protein-coupled P2Y6 pyrimidoceptor protects colorectal cancerous epithelial cells from apoptosis: Is this receptor a novel target against colorectal cancer
Authors: Morgane Placet, Caroline M. Molle, Guillaume Arguin, Sameh Geha, Fernand-Pierre Gendron
Journal: Cancer Research (2016)

Abstract BACKGROUND. Colorectal cancer (CRC) originates from the accumulation of genetic mutations and epigenetic deregulation of tumor suppressor genes (TSGs) and oncogenes, most prominently APC, K-RAS, and TP53. As a result, transformed intestinal epithelial cells (IECs) acquire an evolutionary growth advantage leading to tumor formation. Like other solid tumors, various types of immune cells, and immunomodulatory molecules, including extracellular nucleotides, such as adenosine 5’-triphosphate (ATP) and uridine 5’-diphosphate (UDP), are found in the vicinity of colorectal tumors and promote tumor formation. In this context, activation of the G protein-coupled P2Y6 receptor (P2Y6R) by UDP could contribute to the formation of tumor-promoting microenvironment by modulating the immune response, as we previously reported, but also by coordinating resistance to apoptosis, one of the hallmarks of human CRC. METHODS: Colorectal cancer was induced in P2ry6 gene knockout mice (P2Y6−/−) using azoxymethane along with dextran sulfate sodium challenges. Mice were euthanatized and the number and size of tumor measured. Tissues were fixed and stained prior to histological characterization by a pathologist. In vitro, receptor expression level was determined by qPCR analysis in normal and cancerous IECs as well as from CRC tumor biopsies. Cell growth curves and clonogenic soft agar assays were realized to determine the effect of P2Y6R stimulation on cell growth and tumorigenic potential. Finally, the impact of P2Y6R activation on apoptosis was determined by analyzing apoptosis markers by western blotting. RESULTS: Invalidation of the P2ry6 gene in mice lead to a reduction in the number and size of colorectal tumors, which correlated with the ability of the activated P2Y6R to induce cancerous cell growth in both classical cell growth assays and clonogenic soft agar experiments. Furthermore, P2Y6R stimulation with UDP is not only stimulating cell growth but it also protects colorectal cancerous epithelial cells from TNF-induced apoptosis by a molecular mechanism involving the increase expression of the X-linked inhibitor of apoptosis protein (XIAP). CONCLUSIONS: In this study, we have shown that sustained activation of P2Y6R could contribute to intestinal tumorigenesis by blocking the apoptotic process and by stimulating cell growth. These results suggest that P2Y6R could be a prime target to reduce colorectal carcinogenesis. Citation Format: Morgane Placet, Caroline M. Molle, Guillaume Arguin, Sameh Geha, Fernand-Pierre Gendron. The G protein-coupled P2Y6 pyrimidoceptor protects colorectal cancerous epithelial cells from apoptosis: Is this receptor a novel target against colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4597.