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Targeting Purinergic Receptor P2Y2 Prevents the Growth of Pancreatic Ductal Adenocarcinoma by Inhibiting Cancer Cell Glycolysis

Li-Peng Hu, Xiao-Xin Zhang, Shu-Heng Jiang, Ling-Ye Tao, Qing Li, Li-Li Zhu, Ming-Wei Yang, Yan-Miao Huo, Yong-Sheng Jiang, Guang-Ang Tian, Xiao-Yan Cao, Yan-Li Zhang (+7 others)
2019 Clinical Cancer Research  

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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
more » ... d 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 extracel-lular 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 HIF1a, 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.
doi:10.1158/1078-0432.ccr-18-2297 pmid:30420446 fatcat:65ezrgneyffh5gzlezazucspse
Citation

Li-Peng Hu, Xiao-Xin Zhang, Shu-Heng Jiang, Ling-Ye Tao, Qing Li, Li-Li Zhu, Ming-Wei Yang, Yan-Miao Huo, Yong-Sheng Jiang, Guang-Ang Tian, Xiao-Yan Cao, Yan-Li Zhang, Qin Yang, Xiao-Mei Yang, Ya-Hui Wang, Jun Li, Gary Guishan Xiao, Yong-Wei Sun, Zhi-Gang Zhang. "Targeting Purinergic Receptor P2Y2 Prevents the Growth of Pancreatic Ductal Adenocarcinoma by Inhibiting Cancer Cell Glycolysis." Clinical Cancer Research 25.4 (2019) 1318-1330