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

Xiang Song,Zhaoyun Liu,Zhiyong Yu,Xinzhao Wang

doi:10.3389/fonc.2020.597434

Abstract

Gefitinib resistance in triple negative breast cancer (TNBC) is a growing important concern. Glutathione peroxidase 4 (GPX4) is a main regulator of ferroptosis, which is pivotal for TNBC cell growth. We investigated GPX4-mediated ferroptosis in gefitinib sensitivity in TNBC. Gefitinib resistant TNBC cells MDA-MB-231/Gef and HS578T/Gef were constructed and treated with lentivirus sh-GPX4 and ferroptosis inhibitor ferrostatin-1. GPX4 expression, cell viability and apoptosis were detected. Malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS) levels were evaluated. The levels of ferroptosis-related proteins were detected. Subcutaneous tumor model was established in nude mice, and gefitinib was intraperitoneally injected to evaluate tumor growth, apoptosis, and Ki-67 expression. GPX4 was increased in gefitinib-resistant cells. After silencing GPX4, the inhibition rate of cell viability was increased, the limitation of colony formation ability was reduced, apoptosis rate was increased, and the sensitivity of cells to gefitinib was improved. After silencing GPX4, MDA and ROS production were increased, while GSH was decreased. Silencing GPX4 promoted ferroptosis. Inhibition of GPX4 promoted gefitinib sensitivity by promoting cell ferroptosis. In vivo experiments also revealed that inhibition of GPX4 enhanced the anticancer effect of gefitinib through promoting ferroptosis. Overall, inhibition of GPX4 stimulated ferroptosis and enhanced TNBC cell sensitivity to gefitinib.

Highlights

Breast cancer (BC) is the most common female tumor and leading cause of death among women [1]
This indicated that gefitinib can induce the expression of Glutathione peroxidase 4 (GPX4) in Triple-negative breast cancer (TNBC) cell lines MDA-MB-231 and HS578T
These results suggested that inhibition of GPX4 can increase the sensitivity of TNBC cell lines to gefitinib

Summary

Introduction

Breast cancer (BC) is the most common female tumor and leading cause of death among women [1]. Triple-negative breast cancer (TNBC) accounts for about 20% of BC cases [2]. TNBC is a distinct subtype of BC characterized by aggressive phenotype, high recurrence rates, high visceral metastasis rate, and worse outcomes [3,4,5]. TNBC patients benefit from standard chemotherapy, they still face a high recurrence rate and a high possibility of drug resistance, leaving TNBC a major challenge in the clinic [4, 6]. Clinical trial data show that gefitinib is well tolerated in patients with a wide range of tumor types [7].

Methods

Results

Conclusion