Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, China.
Experimental Teaching Center of Biology and Basic Medical Sciences, Sanquan College of Xinxiang Medical University, Xinxiang, Henan 453003, China.
Oxid Med Cell Longev. 2019 Jun 20;2019:8753413. doi: 10.1155/2019/8753413. eCollection 2019.
Epithelial-mesenchymal transition (EMT) contributes to metastasis and drug resistance; inhibition of EMT may attenuate metastasis and drug resistance. It has been demonstrated that ferritinophagy involves the process of many diseases; however, the relationship between EMT and ferritinophagy was not fully established. Some iron chelators show the ability to inhibit EMT, but whether ferritinophagy plays a role in EMT is largely unknown. To this end, we investigated the effect of a novel iron chelator, DpdtpA (2,2 '-di-pyridylketone dithiocarbamate propionic acid), on EMT in the CT26 cell line. The DpdtpA displayed excellent antitumor (IC = 1.5 ± 0.2 M), leading to ROS production and apoptosis occurrence. Moreover, the ROS production correlated with ferritin degradation. The upregulation of LC3-II and NCOA4 from immunofluorescence and Western blotting analysis revealed that the occurrence of ferritinophagy contributed to ROS production. Furthermore, DpdtpA could induce an alteration both in morphology and in epithelial-mesenchymal markers, displaying significant EMT inhibition. The correlation analysis revealed that DpdtpA-induced ferritinophagy contributed to the EMT inhibition, implying that NCOA4 involved EMT process, which was firstly reported. To reinforce this concept, the ferritinophagic flux (NCOA4/ferritin) in either treated by TGF-1 or combined with DpdtpA was determined. The results indicated that activating ferritinophagic flux would enhance ROS production which accordingly suppressed EMT or implementing the EMT suppression seemed to be through "fighting fire with fire" strategy. Taken together, our data demonstrated that ferritinophagic flux was a dominating driving force in EMT proceeding, and the new finding definitely will enrich our knowledge of ferritinophagy in EMT process.
上皮-间充质转化 (EMT) 促进转移和耐药性；抑制 EMT 可能会减弱转移和耐药性。已经证明铁蛋白吞噬作用涉及许多疾病的过程；然而，EMT 与铁蛋白吞噬作用之间的关系尚未完全确定。一些铁螯合剂表现出抑制 EMT 的能力，但铁蛋白吞噬作用是否在 EMT 中起作用在很大程度上是未知的。为此，我们研究了新型铁螯合剂 DpdtpA（2,2'-二吡啶酮二硫代氨基甲酸盐丙酸）对 CT26 细胞系 EMT 的影响。DpdtpA 显示出优异的抗肿瘤作用（IC = 1.5 ± 0.2 μM），导致 ROS 产生和细胞凋亡发生。此外，ROS 产生与铁蛋白降解相关。免疫荧光和 Western blot 分析显示 LC3-II 和 NCOA4 的上调表明铁蛋白吞噬作用的发生有助于 ROS 产生。此外，DpdtpA 可以诱导形态和上皮-间充质标志物的改变，显示出明显的 EMT 抑制作用。相关性分析表明，DpdtpA 诱导的铁蛋白吞噬作用有助于 EMT 抑制，这表明 NCOA4 参与 EMT 过程，这是首次报道。为了加强这一概念，我们确定了 TGF-1 处理或与 DpdtpA 联合处理后铁蛋白吞噬作用（NCOA4/铁蛋白）的变化。结果表明，激活铁蛋白吞噬作用会增强 ROS 产生，从而抑制 EMT，或者实施 EMT 抑制似乎是通过“以火攻火”的策略。总之，我们的数据表明铁蛋白吞噬作用是 EMT 进展的主要驱动力，这一新发现肯定会丰富我们对 EMT 过程中铁蛋白吞噬作用的认识。
