Activating P2X7 Receptors Increases Proliferation of Human Pancreatic Cancer Cells via ERK1/2 and JNK
Activating P2X7 Receptors Increases Proliferation of Human Pancreatic Cancer Cells via ERK1/2 and JNK
复制标题
DOI：
10.1097/mpa.0000000000001055
复制
发表时间：
2018-05-01
期刊：
影响因子：
2.9
通讯作者：
Lee, Dong Hyeon
中科院分区：
文献类型：
--
作者：
Choi, Ji Hun;Ji, Young Geon;Lee, Dong Hyeon
目的探讨活化的P2X(7)受体对人胰腺癌细胞增殖和生长的影响。方法用溴脱氧尿嘧啶核苷掺入人胰腺癌细胞、MIA-Paca-2和HPAC中检测细胞增殖。用定量逆转录/聚合酶链式反应和/或Western印迹法检测P2受体和信号分子的表达。结果胰腺癌细胞与三磷酸腺苷和2(3)-O-(4-苯甲酰基苯甲酰基)-三磷酸腺苷孵育后，细胞增殖呈剂量依赖性增加。P2受体拮抗剂KN-62和针对P2X(7)受体的小干扰RNA显著降低了ATP的增殖效应。ATP诱导的细胞增殖是由蛋白激酶C、细胞外信号调节蛋白激酶1和2(ERK1/2)和c-jun氨基末端激酶(JNK)介导的，尤其是ATP促进ERK1/2和JNK的磷酸化。P2X(7)受体激活可降低诱导型一氧化氮合酶的表达。结论细胞外核苷酸激活的P2X(7)受体通过ERK1/2和JNK途径促进人胰腺癌细胞的增殖和生长。这支持了P2X(7)受体在胰腺疾病和恢复中的病理生理作用。
Objectives The aim of this study was to investigate the effects of the activated P2X(7) receptors on the proliferation and growth of human pancreatic cancer cells.Methods Proliferation was measured by incorporating bromodeoxyuridine into pancreatic cancer cells, MIA PaCa-2 and HPAC. Expression of P2 receptors and signal molecules was examined using quantitative reverse transcription/polymerase chain reaction and/or Western blot. Proliferative effects of the P2X(7) receptors in vivo were examined using a xenotransplant model of pancreatic cancer cell lines.Results Incubating pancreatic cancer cells with adenosine triphosphate (ATP) and 2(3)-O-(4-Benzoylbenzoyl)ATP resulted in a dose-dependent increase of cell proliferation. The P2 receptor antagonist, KN-62, and small interfering RNA against P2X(7) receptors, significantly decreased the proliferative effects of ATP. The ATP-induced proliferation was mediated by protein kinase C, extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), and c-Jun N-terminal kinase (JNK); specifically, ATP increased the phosphorylation of ERK1/2 and JNK. The expression of inducible nitric oxide synthase was decreased by P2X(7) receptor activation. In a xenotransplant model, applying ATP significantly increased the growth of induced tumors.Conclusions The P2X(7) receptor activation by extracellular nucleotides increased proliferation and growth of human pancreatic cancer cells via ERK1/2 and JNK. This supports the pathophysiological role of P2X(7) receptors in pancreatic disease and recovery.