Bavachin Induces Ferroptosis through the STAT3/P53/SLC7A11 Axis in Osteosarcoma Cells.

Yi Luo,Junming Feng,Zhenming Hu,Miao Lei,Xu Gao,Luetao Zou,German Gil

doi:10.1155/2021/1783485

Abstract

Ferroptosis is a new form of regulated cell death, which is mediated by intracellular iron. Although it is reported that bavachin has antitumour effects on several tumour cells and prompts the reactive oxygen species (ROS) generation, it is unclear whether ferroptosis can be induced by bavachin in osteosarcoma (OS) cells. In this study, we found that bavachin inhibits the viability of MG63 and HOS OS cell lines along with an increase in the ferrous iron level, ROS accumulation, malondialdehyde overexpression, and glutathione depletion. Moreover, iron chelators (deferoxamine), antioxidants (Vit E), and ferroptosis inhibitors (ferrostatin-1 and liproxstatin-1) reverse bavachin-induced cell death. Bavachin also altered the mitochondrial morphology of OS cells, leading to smaller mitochondria, higher density of the mitochondrial membrane, and reduced mitochondrial cristae. Further investigation showed that bavachin upregulated the expression of transferrin receptor, divalent metal transporter-1, and P53, along with downregulating the expression of ferritin light chain, ferritin heavy chain, p-STAT3 (705), SLC7A11, and glutathione peroxidase-4 in OS cells. More importantly, STAT3 overexpression, SLC7A11 overexpression, and pretreatment with pifithrin-α (P53 inhibitor) rescued OS cell ferroptosis induced by bavachin. The results show that bavachin induces ferroptosis via the STAT3/P53/SLC7A11 axis in OS cells.

Highlights

Osteosarcoma (OS) is the most frequent bone tumour in children and adolescents, in addition to being the most common aggressive malignancy originating from mesenchymal cells [1, 2]
Our study revealed that bavachin could induce OS cell death, which was reversed by iron chelator (DFO) and ferroptosis inhibitors (Fer-1, Lip-1, and Vit E)
As a new form of regulated cell death (RCD), ferroptosis significantly differs from other types of cell death, which is due to characteristics of iron-dependence, glutathione peroxidase-4 (GPX4) inhibition, and abnormal lipid peroxidation (LP) [5]

Summary

Introduction

Osteosarcoma (OS) is the most frequent bone tumour in children and adolescents, in addition to being the most common aggressive malignancy originating from mesenchymal cells [1, 2]. Ferroptosis is a new form of regulated cell death (RCD). That is mediated by intracellular iron and is quite different from other forms of cell death, such as apoptosis, autophagy, or necrosis [5]. OHH2O-)2tothgreonuegrhate many reactive oxygen species (ROS) and trigger lipid peroxidation (LP) to induce ferroptosis [6]. ROS generation, and abnormal LP are the hallmarks of ferroptosis [5, 7]. Ferroptosis can be inhibited by iron chelators or antioxidants and activated by some small compounds (erastin), or by inhibiting glutathione peroxidase-4 (GPX4) [9]. SLC7A11, which transports cystine into the cells, enhances glutathione (GSH) synthesis, further promoting the inhibition of ferroptosis by GPX4. P53, as an upstream mediator of SLC7A11, mediates the repression of Oxidative Medicine and Cellular Longevity

Methods

Results

Conclusion