文章摘要
王晓颖,丁 昆,王章定,李爱萍,陈冬寅,周建伟.JWA调控能量代谢重编程抑制胰腺癌细胞迁移[J].南京医科大学学报,2019,(12):1728~1736
JWA调控能量代谢重编程抑制胰腺癌细胞迁移
JWA regulates energy metabolism reprogramming and inhibits migration of pancreatic cancer cell
投稿时间:2019-07-19  
DOI:10.7655/NYDXBNS20191205
中文关键词: JWA  UQCRC2  能量代谢  细胞迁移  胰腺癌
英文关键词: JAC4  UQCRC2  energy metabolism  cell migration  pancreatic cancer
基金项目:国家自然科学基金国际(地区)合作与交流项目(8151001113);南京医科大学胰腺疾病创新团队项目
作者单位
王晓颖 南京医科大学公共卫生学院江苏 南京 211166 
丁 昆 南京医科大学公共卫生学院江苏 南京 211166 
王章定 南京医科大学公共卫生学院江苏 南京 211166 
李爱萍 南京医科大学公共卫生学院江苏 南京 211166 
陈冬寅 南京医科大学药学院江苏 南京 211166 
周建伟 南京医科大学公共卫生学院胰腺研究所江苏 南京 211166 
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中文摘要:
      目的:探讨JWA通过调节细胞能量代谢,抑制胰腺癌细胞迁移的作用及其分子机制。方法:通过基因转染和JWA小分子激动剂JAC4处理人胰腺癌细胞Panc1和Bxpc3,采用划痕实验、穿孔实验、Seahorse XF能量代谢分析仪分别检测细胞迁移能力以及能量代谢水平的改变。用小鼠被动转移模型检测JAC4抑制胰腺癌转移的作用。蛋白免疫印迹法检测相关分子蛋白质表达水平。结果:JWA基因在胰腺癌肿瘤组织与胰腺癌细胞中表达水平显著低于正常;JAC4处理可显著增加JWA表达并抑制胰腺癌细胞迁移,并且抑制小鼠胰腺癌转移并降低血清中乳酸脱氢酶(LDH)水平;JAC4增强肿瘤细胞线粒体有氧呼吸,同时抑制糖酵解;JAC4通过AMPK信号通路正调控FOXO3a,激活线粒体复合物Ⅲ(UQCRC2)的表达,同时下调FAK。结论:JWA通过AMPK/FOXO3a/UQCRC2/FAK信号通路调节细胞能量重编程,进而抑制胰腺癌细胞的迁移。
英文摘要:
      Objective:This study aims to elucidate the role and molecular mechanism of JWA in regulating cell energy metabolism and inhibiting the migration of pancreatic cancer cells. Methods:Human pancreatic cancer Panc1 and Bxpc3 cells were treated with the JWA small molecule agonist JAC4. The assays of wound healing and transwell were used to determine cell migration;the mitochondrial energy metabolisms of cells were measured by Seahorse XF energy metabolism analyzer. The pancreatic cancer cells Panc1 were used to establish series vivo metastatic mice models. Western blotting was performed to determine the levels of protein expression in related molecules. Results:The mRNA expressions of JWA was significantly lower in pancreatic cancer tumor tissues and pancreatic cancer cells compared with that in adjacent normal tissues and normal pancreatic cells;JAC4 inhibited migrations of pancreatic cancer Panc1 and Bxpc3 cells,and inhibited pancreatic cancer metastasis in mice and reduces serum LDH levels. The mechanistic evidences indicated that JAC4 positively regulates FOXO3a through AMPK signaling pathway led to the activation of mitochondrial complex Ⅲ(UQCRC2),and enhanced the oxidative phosphorylation;at the same time,JAC4 suppressed glycolysis of pancreatic cancer cells. Conclusion:The inhibiting role of JAC4 on pancreatic cancer cells was realized by mitochondria metabolic reprogramming through the JWA/AMPK/FOXO3a/UQCRC2/FAK signaling.
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