College of Basic Medical Science, Xinxiang Medical University, Xinxiang, Henan, PR China.
College of Basic Medical Science, Sanquan College of Xinxiang Medical University, Xinxiang, Henan, PR China.
J Inorg Biochem. 2021 May;218:111413. doi: 10.1016/j.jinorgbio.2021.111413. Epub 2021 Mar 4.
Previous studies have shown that epithelial-mesenchymal transition (EMT) involves reactive oxygen species (ROS) production, but how ferritinophagy-mediated ROS production affects EMT status remains obscure. 2,2'-di-pyridylketone hydrazone dithiocarbamate s-butyric acid (DpdtbA), an iron chelator, exhibited interesting antitumor activities against gastric and esophageal cancer cells. As an extension of our previous research, in this paper we presented the effect of DpdtbA on EMT regulation of gastric cancer lines (SGC-7901 and MGC-803) in both normoxic and hypoxic conditions. The data from immunofluorescent and Western blotting analysis revealed that DpdtbA treatment resulted in EMT inhibition along with downregulation of hypoxia-inducible factor (hif-1α), hinting that prolyl hydroxylase 2 (PHD2) was involved. Knockdown of PHD2 significantly attenuated the action of DpdtbA on EMT regulation, supporting that PHD2 involved the EMT modulation. In addition, the inhibition of EMT involved ROS production that stemmed from DpdtbA induced ferritinophagy; while the accumulation of ferrous iron due to ferritinophagy contributed to PHD2 activation and hif-1α degradation. The correlation analysis revealed that ferritinophagic flux was a dominant driving force in determination of the EMT status. Futhermore, the ferritinophagy-mediated ROS production triggered p53 activation. Taken together, All data supported that DpdtbA induced EMT inhibition was through activation of p53 and PHD2/hif-1α pathway.
先前的研究表明上皮-间充质转化（EMT）涉及活性氧（ROS）的产生，但铁蛋白自噬介导的 ROS 产生如何影响 EMT 状态尚不清楚。2,2'-二吡啶酮腙二硫代氨基甲酸盐 s-丁基（DpdtbA），一种铁螯合剂，对胃癌和食管癌细胞表现出有趣的抗肿瘤活性。作为我们先前研究的延伸，在本文中，我们介绍了 DpdtbA 在常氧和缺氧条件下对胃癌细胞系（SGC-7901 和 MGC-803）的 EMT 调节作用。免疫荧光和 Western blot 分析的数据表明，DpdtbA 处理导致 EMT 抑制，同时缺氧诱导因子（hif-1α）下调，提示脯氨酰羟化酶 2（PHD2）参与其中。PHD2 的敲低显著减弱了 DpdtbA 对 EMT 调节的作用，支持 PHD2 参与 EMT 调节。此外，EMT 的抑制涉及 ROS 的产生，这源于 DpdtbA 诱导的铁蛋白自噬；而铁蛋白自噬导致的亚铁积累有助于 PHD2 激活和 hif-1α降解。相关性分析表明，铁蛋白自噬通量是决定 EMT 状态的主要驱动力。此外，铁蛋白自噬介导的 ROS 产生触发了 p53 的激活。综上所述，所有数据均支持 DpdtbA 诱导的 EMT 抑制是通过激活 p53 和 PHD2/hif-1α 通路实现的。
