Targeting Purinergic Receptor P2Y2 Prevents the Growth of Pancreatic Ductal Adenocarcinoma by Inhibiting Cancer Cell Glycolysis
Targeting Purinergic Receptor P2Y2 Prevents the Growth of Pancreatic Ductal Adenocarcinoma by Inhibiting Cancer Cell Glycolysis
复制标题
靶向嘌呤能受体 P2Y2 通过抑制癌细胞糖酵解来预防胰腺导管腺癌的生长
DOI：
10.1158/1078-0432.ccr-18-2297
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发表时间：
2019-02-15
影响因子：
11.5
通讯作者：
Zhang, Zhi-Gang
中科院分区：
文献类型：
--
作者：
Hu, Li-Peng;Zhang, Xiao-Xin;Zhang, Zhi-Gang
目的：大量研究表明，肿瘤微环境成分在肿瘤进展中起着至关重要的作用。因此，阻断肿瘤微环境的支持是预防癌症进展的有希望的方法。我们的目的是确定阻断细胞外ATP-P2RY2轴是否可能是PDAC治疗的潜在治疗方法。实验设计：在264个人PDAC样品中测定P2RY2的表达，并将其与患者存活率相关。分别通过拮抗剂和shRNA抑制人PDAC细胞系中的P2RY2，并测定细胞活力、克隆形成和糖酵解。应用PDAC细胞系的RNA测序来揭示潜在的分子机制。使用多种PDAC小鼠模型来评估P2RY 2抑制对PDAC进展的影响。结果：PDAC患者P2RY2表达上调，与预后不良相关。肿瘤微环境中细胞外ATP增加激活P2RY2促进PDAC生长和糖酵解。进一步的研究表明，激动剂激活的P2RY2通过与Yes1介导的PDGFR串扰触发PI3K/AKT-mTOR信号传导，导致c-Myc和HIF 1 α表达升高，随后增强癌细胞糖酵解。P2RY2的遗传和药理学抑制在皮下和原位异种移植模型中损害肿瘤细胞生长，以及在炎症驱动的PDAC模型中延迟肿瘤进展。此外，当AR-C118925XX（P2RY2受体的选择性拮抗剂）和吉西他滨组合时观察到协同作用，导致异种移植PDAC小鼠的存活延长。结论：这些发现揭示了P2RY2在PDAC代谢重编程中的作用，提示P2RY2可能是PDAC的潜在代谢治疗靶点。
Purpose: Extensive research has reported that the tumor microenvironment components play crucial roles in tumor progression. Thus, blocking the supports of tumor microenvironment is a promising approach to prevent cancer progression. We aimed to determine whether blocking extracellular ATP–P2RY2 axis could be a potential therapeutic approach for PDAC treatment. Experimental Design: Expression of P2RY2 was determined in 264 human PDAC samples and correlated to patient survival. P2RY2 was inhibited in human PDAC cell lines by antagonist and shRNA, respectively, and cell viability, clonogenicity, and glycolysis were determined. RNA sequencing of PDAC cell line was applied to reveal underlying molecular mechanisms. Multiple PDAC mouse models were used to assess the effects of the P2RY2 inhibition on PDAC progression. Results: P2RY2 was upregulated and associated with poor prognosis in PDAC. Activated P2RY2 by increased extracellular ATP in tumor microenvironment promoted PDAC growth and glycolysis. Further studies showed that the agonist-activated P2RY2 triggered PI3K/AKT–mTOR signaling by crosstalk with PDGFR mediated by Yes1, resulting in elevated expression of c-Myc and HIF1α, which subsequently enhanced cancer cell glycolysis. Genetic and pharmacologic inhibition of P2RY2 impaired tumor cell growth in subcutaneous and orthotopic xenograft model, as well as delayed tumor progression in inflammation-driven PDAC model. In addition, synergy was observed when AR-C118925XX, the selective antagonist of P2RY2 receptor, and gemcitabine were combined, resulting in prolonged survival of xenografted PDAC mice. Conclusions: These findings reveal the roles of the P2RY2 in PDAC metabolic reprogramming, suggesting that P2RY2 might be a potential metabolic therapeutic target for PDAC.