p53 Promoted Ferroptosis in Ovarian Cancer Cells Treated with Human Serum Incubated-Superparamagnetic Iron Oxides

Abstract

In this study, we used MTT assays to demonstrate that a combination of SPIO-Serum and wild-type p53 overexpression can reduce ovarian cancer cell viability in vitro. Prussian blue staining and iron assays were used to determine changes in intracellular iron concentration following SPIO-Serum treatment. TEM was used to evaluate any mitochondrial damage induced by SPIO-Serum treatment, and Western blot was used to evaluate the expression of the iron transporter and lipid peroxidation regulator proteins. JC-1 was used to measure mitochondrial membrane potential, and ROS levels were estimated by flow cytometry. Finally, xCT protein expression and mitochondrial ROS levels were confirmed using fluorescence microscopy. Results: SPIO-Serum effectively induced lipid peroxidation and generated abundant toxic ROS. It also facilitated the downregulation of GPX4 and xCT, ultimately resulting in iron-dependent oxidative death. These effects could be reversed by iron chelator DFO and lipid peroxidation inhibitor Fer-1. SPIO-Serum treatment disrupted intracellular iron homeostasis by regulating iron uptake and the cells presented with missing mitochondrial cristae and ruptured outer mitochondrial membranes. Moreover, we were able to show that p53 contributed to SPIO-Serum-induced ferroptosis in ovarian cancer cells. Conclusion: SPIO-Serum induced ferroptosis and overexpressed p53 contributed to ferroptosis in ovarian cancer cells. Our data provide a theoretical basis for ferroptosis as a novel cell death phenotype induced by nanomaterials.

New Insights on Ferroptosis and Gynecological Malignancies

“…In addition, p53-mediated ferroptosis contributes to the effects of metal-based drugs. For example, overexpression of p53 significantly promotes ferroptosis induced by superparamagnetic iron oxides (SPIO) in ovarian cancer cells, then inhibiting the growth of ovarian cancer ( Zhang Y. et al, 2021 ). p53 mutation is associated with the clinical stage and progression of ovarian cancer.…”

A narrative review of mechanisms of ferroptosis in cancer: new challenges and opportunities

“…In a study by Yamada et al (58), following treatment of the normal ovarian cell line OSE/E7/human telomerase reverse transcriptase (hTERT) genome with iron ions, the genome showed the characteristics of ovarian cancer, and normal ovarian cells gradually transformed into cancer cells. Lidocaine can also promote ferroptosis in ovarian cancer by targeting the miR-382-5p/SLC7A11 axis (59), as does superparamagnetic iron oxide cultured in human serum by regulating p53 (60). Additionally, as being a well-tolerated anti-malarial drug, artesunate can also promote ROS and iron-dependent cell death in ovarian cancer cells, but this process can be prevented by the ferroptosis inhibitor F-1 (61).…”

p53 Promotes Ferroptosis in Macrophages Treated with Fe3O4 Nanoparticles

“…After NPs are degraded into iron ions in lysosomes, iron ions induce oxidative stress by generating ROS [31]. Ferroptosis is a type of ROS-dependent regulated cell death [31], mitochondrial damage is the most common feature of this process which caused by intracellular ROS [18]. As determined by flow cytometry (FCM) (Fig.…”

“…Ferroptosis induction is associated with multiple diseases and has recently gained substantial attention as a target for cancer treatment [14]. It is reported that iron oxide NPs induced ferroptosis in few cancer cells [17,18] and ischemic cardiomyocytes [19].…”