The vicious cycle between ferritinophagy and ROS production triggered EMT inhibition of gastric cancer cells was through p53/AKT/mTor pathway

Abstract

Cancer metastasis and resistance for chemotherapeutic agent correlate with epithelial-mesenchymal transition (EMT), while ROS production also involves in the EMT process, However, how autophagy mediated ROS production affects EMT remains unclear. Previous study showed that DpdtC (2,2′-di-pyridylketone hydrazone dithiocarbamate) could induce ferritinophagy in HepG2 cell. To insight into more details that how ferritinophagy affects cellular feature, the SGC-7901and BGC-823 gastric cancer cell lines were used. Interestingly DpdtC treatment resulted in EMT inhibition and was ROS dependent. Similar situation occurred in TGF-β1 induced EMT model, supporting that DpdtC was able to inhibit EMT. Next the ability of DpdtC in ferritinophagy induction was further evaluated. As expected, DpdtC induced ferritinophagy in the absence and presence of TGF-β1. The correlation analysis revealed that an enhanced ferritinophagic flux contributed to the EMT inhibition. In addition, ferritinophagy triggers Fenton reaction, resulting in ROS production which give rise of p53 response, thus the role of p53 was further investigated. DpdtC treatment resulted in upregulation of p53, but, the addition of p53 inhibitor, PFT-α could significantly neutralize the action of DpdtC on ferritinophagy induction and EMT inhibition. Furthermore, autophagy inhibitors or NAC could counteract the action of DpdtC, indicating that ferrtinophagy-mediated ROS played an important role in the cellular events. In addition to upregulation of p53, its down-stream targets, AKT/mTor were also downregulated, supporting that DpdtC induced EMT inhibition was achieved through ferritinophagy-ROS vicious cycle mediated p53/AKT/mTor pathway. And the activation of ferritinophagic flux was the dominant driving force in action of DpdtC in gastric cancer cells.