The Role of Prostaglandin-Endoperoxide Synthase-2 in Chemoresistance of Non-Small Cell Lung Cancer
The Role of Prostaglandin-Endoperoxide Synthase-2 in Chemoresistance of Non-Small Cell Lung Cancer
复制标题
前列腺素内过氧化物合酶2在非小细胞肺癌化疗耐药中的作用
DOI：
10.3389/fphar.2019.00836
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发表时间：
2019-08-08
影响因子：
5.6
通讯作者：
Wu, Xiao-ping
中科院分区：
文献类型：
--
作者：
lin, Xiao-mian;Luo, Wu;Wu, Xiao-ping
前列腺素内过氧化物合酶 2 (PTGS2) 在多种病理过程中发挥重要作用。尽管最近的研究表明PTGS2与化疗耐药密切相关，但PTGS2在非小细胞肺癌（NSCLC）化疗耐药发生过程中的确切作用和潜在机制仍不清楚。在本研究中，我们揭示了PTGS2与NSCLC化疗耐药相关的新分子机制，并提出了PTGS2在NSCLC细胞耐药表型发展过程中的正反馈调节模型。我们的结果表明，顺铂通过 ROS-ERK1/2-NF-κB 信号轴诱导 PTGS2 表达。 PTGS2催化产生的前列腺素E2（PGE2）通过PGE2-EPs-ERK1/2正反馈环进一步增强PTGS2表达，通过上调BCL2表达并随后减弱细胞凋亡来诱导NSCLC细胞的多药耐药。一致地，高水平的 PTGS2 和 BCL2 与 NSCLC 患者的较差生存率密切相关。 PTGS2 的抑制可显着逆转耐药 NSCLC 的体外和体内化疗耐药性。我们的结果表明，PTGS2 可以作为辅助治疗靶点，用于改善耐药 NSCLC 子集中对治疗药物的反应。
The prostaglandin-endoperoxide synthase-2 (PTGS2) plays essential roles in diverse pathological process. Although recent studies implied that PTGS2 was closely related with chemoresistance, the precise roles and the underlying mechanisms of PTGS2 in the developing process of chemoresistance in non-small cell lung cancer (NSCLC) remained elusive. In the present study, we revealed a novel molecular mechanism of PTGS2 implicated in the chemoresistance of NSCLC and proposed a model for the positive feedback regulation of PTGS2 in the process of developing resistance phenotype in NSCLC cells. Our results demonstrated that cisplatin induced PTGS2 expression through the ROS-ERK1/2-NF-κB signaling axis. The prostaglandin E2 (PGE2) derived from PTGS2 catalyzation further strengthened PTGS2 expression via the PGE2-EPs-ERK1/2 positive feedback loop, which induced multidrug resistance of NSCLC cells through up-regulation of BCL2 expression and the subsequent attenuation of cell apoptosis. Consistently, high levels of both PTGS2 and BCL2 were closely associated with poor survival in NSCLC patients. Inhibition of PTGS2 significantly reversed the chemoresistance in the resistant NSCLC in vitro and in vivo. Our results suggested that PTGS2 might be employed as an adjunctive therapeutic target for improving the response to the therapeutic agents in a subset of resistant NSCLC.