Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Biochim Biophys Acta Mol Basis Dis. 2018 May;1864(5 Pt A):1539-1551. doi: 10.1016/j.bbadis.2018.02.008. Epub 2018 Feb 14.
Colorectal tumors are immersed in an array of tumor-promoting factors including extracellular nucleotides such as uridine 5'‑diphosphate (UDP). UDP is the endogenous agonist of the G protein-coupled P2Y receptor (P2YR), which may contribute to the formation of a tumor-promoting microenvironment by coordinating resistance to apoptosis. Colorectal cancer (CRC) was chemically induced in P2ry6 knockout (P2ry6) mice using azoxymethane and dextran sulfate sodium challenges. Mice were euthanatized and their tumor load determined. Fixed tissues were stained for histological and immunohistochemistry analysis. Tumoroids were also prepared from CRC tumors resected from P2ry6 mice to determine the role of P2YR in resistance to apoptosis, whereas HT29 carcinoma cells were used to elucidate the signaling mechanism involved in P2YR anti-apoptotic effect. P2ry6 mice developed a reduced number of colorectal tumors with apparent tumors having smaller volumes. Overall dysplastic score was significantly lower in P2ry6 animals. Stimulation of P2YR with the selective agonist MRS2693 protected HT-29 cells from TNFα-induced apoptosis. This protective effect was mediated by the stabilizing phosphorylation of the X-linked inhibitor of apoptosis protein (XIAP) by AKT. Using CRC-derived tumoroids, P2YR activation was found to contribute to chemoresistance since addition of the P2YR agonist MRS2693 significantly prevented the cytotoxic effect of 5-fluorouracil. The present study shows that sustained activation of P2YR may contribute to intestinal tumorigenesis by blocking the apoptotic process and by contributing to chemoresistance, a substantial concern in the treatment of patients with CRC. These results suggest that P2YR may represent a prime target for reducing colorectal carcinogenesis.
结直肠肿瘤浸润在一系列肿瘤促进因子中，包括细胞外核苷酸，如尿苷 5'-二磷酸（UDP）。UDP 是 G 蛋白偶联 P2Y 受体（P2YR）的内源性激动剂，通过协调对细胞凋亡的抵抗，可能有助于形成促进肿瘤的微环境。使用偶氮甲烷和葡聚糖硫酸钠挑战，在 P2ry6 基因敲除（P2ry6）小鼠中化学诱导结直肠癌（CRC）。处死小鼠并确定其肿瘤负荷。固定组织进行组织学和免疫组织化学分析。还从 P2ry6 小鼠切除的 CRC 肿瘤中制备肿瘤球，以确定 P2YR 在抵抗细胞凋亡中的作用，而 HT29 癌细胞则用于阐明涉及 P2YR 抗细胞凋亡作用的信号转导机制。P2ry6 小鼠结直肠肿瘤数量减少，明显肿瘤体积较小。P2ry6 动物的整体发育不良评分显著降低。用选择性激动剂 MRS2693 刺激 P2YR 可保护 HT-29 细胞免受 TNFα 诱导的细胞凋亡。这种保护作用是通过 AKT 稳定磷酸化 X 连锁凋亡抑制蛋白（XIAP）介导的。使用源自 CRC 的肿瘤球，发现 P2YR 激活有助于化学抗性，因为添加 P2YR 激动剂 MRS2693 可显著防止氟尿嘧啶的细胞毒性作用。本研究表明，P2YR 的持续激活可能通过阻断细胞凋亡过程并有助于化学抗性来促进肠道肿瘤发生，这是 CRC 患者治疗中的一个重要问题。这些结果表明，P2YR 可能成为减少结直肠癌变的主要靶标。
