The DpdtbA induced EMT inhibition in gastric cancer cell lines was through ferritinophagy-mediated activation of p53 and PHD2/hif-1α pathway

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 (hif1 alpha), 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-1 alpha 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-1 alpha pathway.

Automated summary

Previous studies have suggested that ferritinophagy-mediated ROS production affects EMT status, and the iron chelator DpdtbA inhibits EMT in gastric cancer cells through activation of the p53 and PHD2/hif-1 alpha pathway.