Synergistic Effect of Erastin Combined with Nutlin-3 on Vestibular Schwannoma Cells as p53 Modulates Erastin-Induced Ferroptosis Response

Abstract

Vestibular schwannoma (VS) is a rare neurotology neoplasm that results in partial neurological defects. As we know, a comprehensive understanding of basic mechanisms and targeted therapy is vital for disease management. In VS, p53 has been proved to suppress tumor progression via a cooperative with the key protein, merlin, as well as regulation of the cell cycle. However, there are more potential mechanisms of p53 in VS needed to exploit. First, via genome-wide RNA expression analysis, we identified differentially expressed genes in VS compared with normal nerves, and then, bioinformatics analyses were used to analyze these differential expression data and suggested a high level of enrichment of cysteine and glutathione metabolism pathways in VS. Meanwhile, we observed a downregulation of SLC7A11/xCT, a component of the cystine/glutamate antiporter (also known as system x _c ⁻) involved in cystine uptake. Next, for a deeper study, our group extracted tumor cells from vestibular schwannoma tissues and established two immortalized cell lines named JEI-001 and JEI-002. Secondly, in our established cells, we demonstrated that ferroptosis participated in erastin-induced growth inhibition. As a novel cell death process, ferroptosis driven by iron-mediated lipid reactive oxygen species (lipid ROS), as well as cysteine and glutathione metabolism. Furthermore, ferroptosis contributes to the inhibitory effects of tumor suppressor p53. Here, we show that p53 sensitizes schwannoma cells to ferroptosis by repressing expression of SLC7A11/xCT. Finally, erastin combined with Nutlin-3, which s to p53 activation, triggered antitumor effects of ferroptosis on the growth of schwannoma cells in vitro. These findings present potential mechanism of p53 in schwannomas and raise the possibility of treatment strategies directed against this pathogenesis.