The Possible Connection of Two Dual Function Processes: The Relationship of Ferroptosis and the JNK Pathway

Abstract

Ferroptosis represents a typical process that has dual functions in cell fate decisions since the reduction and/or inhibition of ferroptosis is desirable for the therapies of diseases such as neurological disorders, localized ischemia-reperfusion, kidney injury, and hematological diseases, while the enhanced ferroptosis of cancer cells may benefit patients with cancer. The JNK pathway also has a real dual function in the fate of cells. Multiple factors suggest a potential link between the ferroptotic and JNK pathways; (i) both processes are ROS mediated; (ii) both can be inhibited by lipid peroxide scavengers; (iii) RAS mutations may play a role in the initiation of both pathways. We aimed to investigate the possible link between ferroptosis and the JNK pathway. Interestingly, JNK inhibitor co-treatment could enhance the cancer cytotoxic effect of the ferroptosis inducers in NRAS and KRAS mutation-harboring cells (HT-1080 and MIA PaCa-2). Since cancer’s cytotoxic effect from the JNK inhibitors could only be suspended by the ferroptosis inhibitors, and that sole JNK-inhibitor treatment did not affect cell viability, it seems that the JNK inhibitors “just” amplify the effect of the ferroptosis inducers. This cancer cell death amplifying effect of the JNK inhibitors could not be observed in other oxidative stress-driven cell deaths. Hence, it seems it is specific to ferroptosis. Finally, our results suggest that GSH content/depletion could be an important candidate for switching the anti-cancer effect of JNK inhibitors.

Cell density impacts the susceptibility to ferroptosis by modulating IRP1‐mediated iron homeostasis

“…There are clear discrepancies in ferroptosis susceptibility even in the same cell line across various reports (Asperti et al, 2021;Dixon et al, 2012;Nishigori et al, 2017;Varga et al, 2022;Yan et al, 2022;Yuan et al, 2022), and such variations significantly have an impact on the outcome of an experiment. Our study shows that cell density mediates variations in resistance to ferroptosis by influencing the levels of iron, which was previously underappreciated.…”

“…However, even when using the same cell line, there are inconsistent reports. As an example, the three reports (Dixon et al, 2012;Nishigori et al, 2017;Varga et al, 2022) demonstrate varying sensitivities of HT1080 cells to ferroptosis inducers. Coincidentally, HepG2 cells also exhibit different ferroptosis sensitivities in different reports (Asperti et al, 2021;Yan et al, 2022;Yuan et al, 2022).…”