DpdtC-Induced EMT Inhibition in MGC-803 Cells Was Partly through Ferritinophagy-Mediated ROS/p53 Pathway

Abstract

Epithelial-mesenchymal transition (EMT) is a cellular process in which epithelial cells are partially transformed into stromal cells, which endows the polarized epithelium cells more invasive feature and contributes cancer metastasis and drug resistance. Ferritinophagy is an event of ferritin degradation in lysosomes, which contributes Fenton-mediated ROS production. In addition, some studies have shown that ROS participates in EMT process, but the effect of ROS stemmed from ferritin degradation on EMT has not been fully established. A novel iron chelator, DpdtC (2,2′-di-pyridylketone dithiocarbamate), which could induce ferritinophagy in HepG2 cell in our previous study, was used to investigate its effect on EMT in gastric cancer cells. The proliferation assay showed that DpdtC treatment resulted in growth inhibition and morphologic alteration in MGC-803 cell (IC50=3.1±0.3 μM), and its action involved ROS production that was due to the occurrence of ferritinophagy. More interestingly, DpdtC could also inhibit EMT, leading to the upregulation of E-cadherin and the downregulation of vimentin; however, the addition of NAC and 3-MA could attenuate (or neutralize) the action of DpdtC on ferritinophagy induction and EMT inhibition, supporting that the enhanced ferritinophagic flux contributed to the EMT inhibition. Since the degradation of ferritin may trigger the production of ROS and induce the response of p53, we next studied the role of p53 in the above two-cell events. As expected, an upregulation of p53 was observed after DpdtC insulting; however, the addition of a p53 inhibitor, PFT-α, could significantly attenuate the action of DpdtC on ferritinophagy induction and EMT inhibition. In addition, autophagy inhibitors or NAC could counteract the effect of DpdtC and restore the level of p53 to the control group, indicating that the upregulation of p53 was caused by ferritinophagy-mediated ROS production. In conclusion, our data demonstrated that the inhibition of EMT induced by DpdtC was realized through ferritinophagy-mediated ROS/p53 pathway, which supported that the activation of ferritinophagic flux was the main driving force in EMT inhibition in gastric cancer cells, and further strengthening the concept that NCOA4 participates in EMT process.

Caryophyllene Oxide Induces Ferritinophagy by Regulating the NCOA4/FTH1/LC3 Pathway in Hepatocellular Carcinoma

“…Caryophyllene oxide also influenced their cell morphology, affected their cell migration, and increased cell apoptosis and death. According to the findings of several studies ( Hou et al, 2016 ; Feng et al, 2020 ; Fuhrmann et al, 2020 ; Yang et al, 2021 ), the occurrence of ferroptosis is closely related to oxidative stress. Ferroptosis is characterized by the buildup of lipid peroxidation to deadly levels.…”

The critical role of ferritinophagy in human disease

“…After iron enters the circulation, it is oxidized by hephaestin or ceruloplasmin to Fe 3+ , which binds to transferrin. Additionally, ferritin can be transported by the Prominin-2 polyvesicle–exosome pathway out of the cell when the cell is overloaded with iron ( Gao et al, 2016 ; Zhou et al, 2018 ; Feng H et al, 2020 ); and 3) iron storage—Fe 2+ enters the cells to form cytoplasmic labile iron pool (LIP) ( Kakhlon and Cabantchik, 2002 ; Feng J et al, 2020 ). One part of Fe 2+ is stored as ferritin, and the other part is used for various biochemical processes.…”

The revival of dithiocarbamates: from pesticides to innovative medical treatments

“…DSF and DTCs, in combination with metal ions, can induce ROS production through the Fenton and Haber Weiss reaction, and also by inhibiting antioxidants such as superoxide dismutase and glutathione ( Marikovsky et al., 2002 ; Skrott and Cvek, 2012 ). A recent article showed that a dipyridylhydrazone DTC induced ferritinophagy by mobilizing iron from ferritin and mediating the ROS/p53 pathway, resulting in the inhibition of gastric cancer cell line proliferation ( Feng et al., 2020 ; Huang et al., 2018 ).…”