Sinha, B.K.; Carri, M.; Brown, S.M.; Siver, B.; Tokar, E.J.; Bortner, C.D. Molecular Mechanisms of Erastin-Induced Ferroptosis in Human Ovarian Tumor Cells. Preprints2024, 2024021608. https://doi.org/10.20944/preprints202402.1608.v1
APA Style
Sinha, B.K., Carri, M., Brown, S.M., Siver, B., Tokar, E.J., & Bortner, C.D. (2024). Molecular Mechanisms of Erastin-Induced Ferroptosis in Human Ovarian Tumor Cells. Preprints. https://doi.org/10.20944/preprints202402.1608.v1
Chicago/Turabian Style
Sinha, B.K., Erik J Tokar and Carl D Bortner. 2024 "Molecular Mechanisms of Erastin-Induced Ferroptosis in Human Ovarian Tumor Cells" Preprints. https://doi.org/10.20944/preprints202402.1608.v1
Abstract
Erastin (ER) induces cell death by utilizing the process of ferroptosis via generation of reactive oxygen species (ROS). Ferroptosis is characterized by accumulation of ROS within the cell, leading to an iron-dependent oxidative damage-mediated cell death. Here, we have examined ferroptosis-dependent mechanism(s) of cytotoxicity of ER in K-RAS mutant human ovarian tumor OVCAR-8 and NCI/ADR-RES cell lines. We used these cell lines to decipher the mechanisms of ER as NCI/ADR-RES cells express higher activities of SOD, glutathione peroxidase and transferases than OVCAR-8 cells. We found that ER was equally cytotoxic to both cells; ER formed more ROS in OVCAR-8 cells than in NIH/ADR-RES cells. Ferrostatin-1, an inhibitor of ferroptosis, inhibited ER-induced cell death in both cell lines. In contrast, RSL3 (RAS-selective lethal 3), an inducer of ferroptosis, significantly enhanced cell death in both cell lines. ER induced significant lipid peroxidation only in OVCAR-8 cells. We found that RSL3 was more cytotoxic to NCI/ADR-RES cells and significantly enhanced ER-induced lipid peroxidation in both cells, indicating GPX4 was involved in the process of ER-mediated ferroptosis. ER treatment also differentially modulated several ferroptosis related genes (e.g., HMOX1/OH1, and CHAC1) in these cells, indicating ER-induced cell death may be mediated differently in OVCAR-8 and NCI/ADR-RES ovarian cells. Our studies suggest that combinations of ER and RSL3 may contribute significantly to the treatment of ovarian cancers, including those that are resistant to other therapeutic agents due to the presence of P-gp or tumors with Ras mutation in the clinic. ER induced ferroptosis may also be an important treatment modality for resistant tumors expressing MDR1 in the clinic.
Keywords
Erastin; Ferroptosis; Ovarian Tumor calls; RSL3; Reactive Oxygen Species
Subject
Medicine and Pharmacology, Medicine and Pharmacology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
