GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis

Qiujie Wang,Qiang Xue,Qingzhu Gao,Cheng Bin,Ni Tang,Ailong Huang,Kai Wang

doi:10.1038/s41419-021-03718-4

Abstract

Increasing evidence supports that ferroptosis plays an important role in tumor growth inhibition. Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, has been shown to induce ferroptosis in hepatocellular carcinoma (HCC). However, some hepatoma cell lines are less sensitive to sorafenib-induced ferroptotic cell death. Glutathione S-transferase zeta 1 (GSTZ1), an enzyme in the catabolism of phenylalanine, suppresses the expression of the master regulator of cellular redox homeostasis nuclear factor erythroid 2-related factor 2 (NRF2). This study aimed to investigate the role and underlying molecular mechanisms of GSTZ1 in sorafenib-induced ferroptosis in HCC. GSTZ1 was significantly downregulated in sorafenib-resistant hepatoma cells. Mechanistically, GSTZ1 depletion enhanced the activation of the NRF2 pathway and increased the glutathione peroxidase 4 (GPX4) level, thereby suppressing sorafenib-induced ferroptosis. The combination of sorafenib and RSL3, a GPX4 inhibitor, significantly inhibited GSTZ1-deficient cell viability and promoted ferroptosis and increased ectopic iron and lipid peroxides. In vivo, the combination of sorafenib and RSL3 had a synergic therapeutic effect on HCC progression in Gstz1−/− mice. In conclusion, this finding demonstrates that GSTZ1 enhanced sorafenib-induced ferroptosis by inhibiting the NRF2/GPX4 axis in HCC cells. Combination therapy of sorafenib and GPX4 inhibitor RSL3 may be a promising strategy in HCC treatment.

Highlights

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide[1]
We previously found that Glutathione S-transferase zeta 1 (GSTZ1) was poorly expressed in HCC, and GSTZ1 deficiency could lead to metabolite succinylacetone accumulation and thereby activate the nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway[19,20]
We found that the SR cells became less sensitive to sorafenib (Fig. 1B, C), and the growth rate was remarkably increased (Fig. 1D)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide[1]. In the early stages of HCC, curative treatment can be achieved with tumor ablation, resection, or liver transplantation[2]. The majority of HCC patients are already in the middle-late stage when diagnosed; the optimal period for curative treatment is missed. A multi-target kinase inhibitor, has been confirmed to Ferroptosis is a newly described programmed form of cell death characterized by iron-dependent accumulation of lipid peroxides to lethal amounts, different from the traditional cell death forms of apoptosis, necroptosis, and autophagy[5]. Growing evidence indicates that ferroptosis can be induced by inhibiting cystine/glutamate transporter (SLC7A11/xCT) activity, downregulating glutathione peroxidase 4 (GPX4), and accumulating iron and lipid. Official journal of the Cell Death Differentiation Association. Wang et al Cell Death and Disease (2021)12:426 reactive oxygen species (ROS)[6,7,8]. Recent reports have shown that sorafenib could induce ferroptosis; targeting ferroptosis to improve sorafenib therapy might be a new promising strategy for HCC treatment[9,10,11]

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Conclusion