Metformin inhibits castration-induced EMT in prostate cancer by repressing COX2/PGE2/STAT3 axis
Metformin inhibits castration-induced EMT in prostate cancer by repressing COX2/PGE2/STAT3 axis
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二甲双胍通过抑制 COX2/PGE2/STAT3 轴抑制前列腺癌去势诱导的 EMT
DOI：
10.1016/j.canlet.2016.12.031
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发表时间：
2017-03-28
期刊：
影响因子：
9.7
通讯作者：
Jiang, Jun
中科院分区：
文献类型：
--
作者：
Tong, Dali;Liu, Qiuli;Jiang, Jun
去势是晚期前列腺癌的标准治疗方法，但由于其严重的复发和转移，其疗效有限。炎症信号通路的激活和上皮细胞间充质转化(EMT)的启动与肿瘤的耐药、复发和转移密切相关。在本研究中，我们通过下调间质标志物N-cadherin、Vimentin和Twist以及上调上皮细胞E-cadherin来抑制EMT，从而证明二甲双胍能够抑制前列腺癌的迁移和侵袭。在我们的动物模型和前列腺癌患者中也观察到了这些影响。此外，我们还通过抑制COX2、PGE2和磷酸化STAT3的水平，展示了二甲双胍对EMT相关基因表达的影响。此外，灭活COX2取消了二甲双胍的调节作用，外源性PGE2能够增强STAT3的磷酸化和EMT生物标记物的表达。我们认为二甲双胍通过靶向COX2/PGE2/STAT3轴来抑制前列腺癌的EMT和转移。这些发现表明，二甲双胍本身或与其他抗癌药物联合使用可以作为一种抗转移治疗。(C)2016爱思唯尔爱尔兰有限公司。保留所有权利。
Castration is the standard therapeutic treatment for advanced prostate cancer but with limited benefit due to the profound relapse and metastasis. Activation of inflammatory signaling pathway and initiation of epithelial mesenchymal transition (EMT) are closely related to drug resistance, tumor relapseas well as metastasis. In this study, we demonstrated that metformin is capable of inhibiting prostate cancer cell migration and invasion by repressing EMT evidenced by downregulating the mesenchymal markers N-cadherin, Vimentin, and Twist and upregulating the epithelium E-cadherin. These effects have also been observed in our animal model as well as prostate cancer patients. In addition, we showed the effects of metformin on the expression of genes involved in EMT through repressing the levels of COX2, PGE2 and phosphorylated STAT3. Furthermore, inactivating COX2 abolishes metformin's regulatory effects and exogenously administered PGE2 is capable of enhancing STAT3 phosphorylation and expression of EMT biomarker. We propose that metformin represses prostate cancer EMT and metastasis through targeting the COX2/PGE2/STAT3 axis. These findings suggest that metformin by itself or in combination with other anticancer drugs could be used as an anti-metastasis therapy. (C) 2016 Elsevier Ireland Ltd. All rights reserved.