The induction of ferroptosis by impairing STAT3/Nrf2/GPx4 signaling enhances the sensitivity of osteosarcoma cells to cisplatin

Abstract

Recent studies have indicated that promoting ferroptosis is a promising approach to attenuate drug resistance of cancer cells. Hence, this study aimed to induce ferroptosis in osteosarcoma cells, thereby increasing the sensitivity to cisplatin. Osteosarcoma cells MG63 and Saos-2 were incubated with increasing doses of cisplatin to generate cisplatin-resistant strains, MG63/DDP and Saos-2/DDP. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays were performed to evaluate cell proliferation and cell death, respectively. Malondialdehyde (MDA), reactive oxygen species (ROS), and lipid oxidation in cells were measured to evaluate the degree of cell ferroptosis. MG63/ DDP and Saos-2/DDP cells showed increased viability and decreased death rate compared with MG63 and Saos-2 cells, respectively, upon cisplatin treatment. Western blotting analysis indicated that protein levels of p-STAT3 (Ser727), nuclear factor erythroid 2-related factor 2 (Nrf2), and glutathione peroxidase 4 (GPx4) in drug-resistant strains increased significantly in response to cisplatin. Co-treatment with cisplatin and agonists of ferroptosis, Erastin, and RSL3, remarkably increased MDA, ROS, lipid oxidation, and sensitivity to cisplatin, in MG63/DDP and Saos-2/DDP cells. Similar results were observed by co-treatment of cells with cisplatin and a STAT3 inhibitor. The reduction of protein levels of p-STAT3 (Ser727), Nrf2, and GPx4 in MG63/DDP and Saos-2/DDP cells resulted in increased ferroptosis and sensitivity to cisplatin. These results indicate that cisplatin-resistant osteosarcoma cells inhibited ferroptosis after exposure to low doses of cisplatin. However, ferroptosis agonists and STAT3 inhibitor reactivated ferroptosis in the cells and consequently increased sensitivity to cisplatin. This study demonstrates a new approach to attenuate resistance of osteosarcoma to cisplatin in vitro.

Erastin Reverses ABCB1-Mediated Docetaxel Resistance in Ovarian Cancer

“…The anticancer property of erastin has been proved to be incredibly effective in a variety of cancers, such as liver cancer, lung cancer, gastric cancer, breast cancer, osteosarcoma, etc. (21)(22)(23)(24). Combination therapy of erastin with other chemotherapeutic agents like cisplatin shows a significant synergistic effect in a number of cancers.…”

Inhibition of ferroptosis protects House Ear Institute‐Organ of Corti 1 cells and cochlear hair cells from cisplatin‐induced ototoxicity

“…[39][40][41] For example, under the stress stimuli, the promotion of ferroptosis by ferroptosis inducer reactivated ferroptosis in osteosarcoma cells and consequently enhanced the sensitivity to cisplatin. 39 According to the earlier observation of Initially, we proved that iron overload could be induced by cisplatin exposure. We employed two assays detecting Fe 2+ : the FerroOrange staining reflects intracellular Fe 2+ and the Mito-FerroGreen staining assesses mitochondrial Fe 2+ , respectively.…”

Role of GPX4-Mediated Ferroptosis in the Sensitivity of Triple Negative Breast Cancer Cells to Gefitinib

“…Increasing evidences have indicated that promoting ferroptosis is a promising approach to attenuate drug resistance in cancer chemotherapy [37,38]. Given the therapeutic promise for inducing ferroptosis in drug-resistant cancers, a potent GPX4 inhibitor is paramount [39,40].…”