Ferroptotic agent‐induced endoplasmic reticulum stress response plays a pivotal role in the autophagic process outcome

• Published in: Journal of cellular physiology Vol. 235; no. 10; pp. 6767 - 6778
• Main Authors: Lee, Young‐Sun, Kalimuthu, Kalishwaralal, Seok Park, Yong, Makala, Hima, Watkins, Simon C., Choudry, M. Haroon A., Bartlett, David L., Tae Kwon, Yong, Lee, Yong J.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.10.2020
• Subjects: Apoptosis; Apoptosis - physiology; Artesunate; Autophagosomes - metabolism; Autophagosomes - physiology; Autophagy; Autophagy - physiology; Bortezomib; Cell death; Cell Line, Tumor; Cellular stress response; Chloroquine; Endoplasmic reticulum; endoplasmic reticulum stress; Endoplasmic Reticulum Stress - physiology; Ferroptosis; Ferroptosis - physiology; Gene deletion; Glutathione; Glutathione - metabolism; HCT116 Cells; Heme; Heme Oxygenase-1 - metabolism; Humans; Lipid peroxidation; Lipid Peroxidation - physiology; Lipids; Mortality; Oxidation-Reduction; Oxidative stress; Oxidative Stress - physiology; Oxygenase; Peroxidation; Phagocytosis; Signal Transduction - physiology; autophagy; ferroptosis; glutathione; endoplasmic reticulum stress
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.29571

Ferroptosis has been reported as a unique form of cell death. However, in recent years, researchers have increasingly challenged the uniqueness of ferroptosis compared to other types of cell death. In this study, we examined whether ferroptosis shares cell death pathways with other types of cell death, especially autophagy, via the autophagic process. Here, we observed that ferroptosis inducers (artesunate [ART] and erastin [ERA]) and autophagy inducers (bortezomib [BOR] and XIE62‐1004) led to autophagosome formation via the endoplasmic reticulum (ER) stress response. Unlike XIE62‐1004, ART, ERA, and BOR, which affect glutathione production or utilization, induced oxidative stress responses—an increase in the levels of heme oxygenase‐1 and lipid peroxidation. Oxidative stress responses were attenuated by deletion of autophagy‐related gene‐5 or treatment with autophagy inhibitors (bafilomycin and chloroquine). Our studies provide an overview of common death pathways—the ER stress response‐associated autophagic process in ferroptosis and autophagy. We also highlight the role played by glutathione redox system in the outcome of the autophagic process. The role played by glutathione redox system in the outcome of the autophagic process.