Tong Dali, Liu Qiuli, Liu Gaolei, Xu Jing, Lan Weihua, Jiang Yao, Xiao Hualiang, Zhang Dianzheng, Jiang Jun
Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China.
Department of Pathology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China.
Cancer Lett. 2017 Mar 28;389:23-32. doi: 10.1016/j.canlet.2016.12.031. Epub 2016 Dec 30.
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.
去势是晚期前列腺癌的标准治疗方法，但由于复发和转移严重，疗效有限。炎症信号通路的激活和上皮-间质转化（EMT）的启动与耐药性、肿瘤复发以及转移密切相关。在本研究中，我们证明二甲双胍能够通过抑制EMT来抑制前列腺癌细胞的迁移和侵袭，这表现为下调间充质标志物N-钙黏蛋白、波形蛋白和Twist以及上调上皮标志物E-钙黏蛋白。在我们的动物模型以及前列腺癌患者中也观察到了这些作用。此外，我们发现二甲双胍通过抑制COX2、PGE2和磷酸化STAT3的水平来影响参与EMT的基因表达。此外，使COX2失活可消除二甲双胍的调节作用，而外源性给予PGE2能够增强STAT3磷酸化和EMT生物标志物的表达。我们提出二甲双胍通过靶向COX2/PGE2/STAT3轴来抑制前列腺癌的EMT和转移。这些发现表明，二甲双胍单独使用或与其他抗癌药物联合使用可作为一种抗转移疗法。
