The curcumin analogue WZ35 affects glycolysis inhibition of gastric cancer cells through ROS-YAP-JNK pathway
The curcumin analogue WZ35 affects glycolysis inhibition of gastric cancer cells through ROS-YAP-JNK pathway
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DOI：
10.1016/j.fct.2020.111131
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发表时间：
2020-03-01
影响因子：
4.3
通讯作者：
Wang, Lihua
中科院分区：
文献类型：
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作者：
Chen, Tongke;Zhao, Liqian;Wang, Lihua
为探讨WZ35的抗肿瘤活性及其可能的分子机制，采用生物信息学分析和苏木精-伊红（HE）染色法检测胃癌组织中Yes-associated-protein （YAP）水平。细胞计数试剂盒-8 （CCK-8）检测细胞活力。流式细胞术检测细胞凋亡。采用海马生物能量分析仪研究了氧消耗和有氧糖酵解速率的变化。SiRNA转染用于沉默内源性YAP。Western blot检测指示蛋白。我们发现WZ35对胃癌细胞的抗肿瘤作用强于姜黄素。在机制上，我们的研究表明WZ35通过下调胃癌细胞中YAP，抑制糖酵解，诱导活性氧（ROS）的产生，从而激活Jun n -末端激酶（JNK）。ROS介导的YAP下调和JNK激活受到糖酵解的调节。消除ROS的产生可显著减弱WZ35诱导的抗肿瘤活性以及YAP下调和JNK激活。同样，JNK抑制剂显著逆转WZ35诱导的胃癌细胞抗肿瘤活性。我们的研究揭示了WZ35通过ROS-YAP-JNK途径抑制糖酵解的抗胃癌新机制。WZ35可能是一种潜在的治疗胃癌的药物。
To investigate the anti-tumor activities of WZ35 and its possible molecular mechanism, bioinformatics analysis and the hematoxylin-eosin (HE) staining were applied to evaluate the Yes-associated-protein (YAP) level in gastric cancer. Cell counting kit-8 (CCK-8) was used to examine cell viability. Apoptosis was determined by flow cytometry analysis. Seahorse bioenergetics analyzer was used to investigate the alteration of oxygen consumption and aerobic glycolysis rate. SiRNA transfection was applied to silence endogenous YAP. Western blot was performed to detect indicated proteins. We found that treatment of gastric cancer cells with WZ35 exerted stronger anti-tumor activities than curcumin. Mechanistically, our research showed that WZ35 inhibited glycolysis, and induced reactive oxygen species (ROS) generation, resulting in Jun N-terminal Kinase (JNK) activation through downregulation of YAP in gastric cancer cells. ROS mediated YAP downregulation and JNK activation was regulated by glycolysis. Abrogation of ROS production markedly attenuated WZ35 induced anti-tumor activities as well as YAP downregulation and JNK activation. Similarly, the JNK inhibitor significantly reversed WZ35 induced anti-tumor activities in gastric cancer cells. Our study reveals a novel anti-gastric cancer mechanism of WZ35 by inhibiting glycolysis through the ROS-YAP-JNK pathway. WZ35 might be a potential therapeutics for the treatment of gastric cancer.