Oxidative Stress Activated by Sorafenib Alters the Temozolomide Sensitivity of Human Glioma Cells Through Autophagy and JAK2/STAT3-AIF Axis

Jianwei Wei,Weiwei Wang,Xueyuan Li,Zhengfeng Wang,Liwei Ma,Xiaoge Liu,Yongjie Yuan,Xianzhi Liu,Junhu Wan

doi:10.3389/fcell.2021.660005

Abstract

The development of temozolomide (TMZ) resistance in glioma leads to poor patient prognosis. Sorafenib, a novel diaryl urea compound and multikinase inhibitor, has the ability to effectively cross the blood-brain barrier. However, the effect of sorafenib on glioma cells and the molecular mechanism underlying the ability of sorafenib to enhance the antitumor effects of TMZ remain elusive. Here, we found that sorafenib could enhance the cytotoxic effects of TMZ in glioma cells in vitro and in vivo. Mechanistically, the combination of sorafenib and TMZ induced mitochondrial depolarization and apoptosis inducing factor (AIF) translocation from mitochondria to nuclei, and this process was dependent on STAT3 inhibition. Moreover, the combination of sorafenib and TMZ inhibited JAK2/STAT3 phosphorylation and STAT3 translocation to mitochondria. Inhibition of STAT3 activation promoted the autophagy-associated apoptosis induced by the combination of sorafenib and TMZ. Furthermore, the combined sorafenib and TMZ treatment induced oxidative stress while reactive oxygen species (ROS) clearance reversed the treatment-induced inhibition of JAK2/STAT3. The results indicate that sorafenib enhanced the temozolomide sensitivity of human glioma cells by inducing oxidative stress-mediated autophagy and JAK2/STAT3-AIF axis.

Highlights

Glioma is a common malignant tumor of the central nervous system (CNS) that accounts for approximately 45% of all intracranial tumors (Li et al, 2020)
These results suggest that sorafenib inhibited the growth and induced the apoptosis of glioma cells in a time- and dose-dependent manner
These results suggest that the combination of sorafenib and TMZ triggered glioma cell apoptosis through the mitochondrial-associated pathway and was associated with the nuclear aggregation of apoptosis inducing factor (AIF)

Summary

Introduction

Glioma is a common malignant tumor of the central nervous system (CNS) that accounts for approximately 45% of all intracranial tumors (Li et al, 2020). The development of TMZ resistance promotes the survival of glioma cells and leads to poor prognosis of patients. DNA repair systems, including DNA mismatch repair (MMR) (Perazzoli et al, 2015) and base excision repair (BER) (Tang et al, 2011), play important roles in the mechanisms of TMZ resistance. Epidermal growth factor receptor (EGFR) (Chong et al, 2015), murine double minute 2 (Mdm2) (Costa et al, 2013) and the PI3K/AKT/mTOR pathway (Liu et al, 2015) are involved in TMZ resistance mechanisms. Reports have concluded that TMZ could kill most of the original tumor cells; tumor stem (initiating) cells are considered to naturally resist to radiochemotherapy and represent a primary cause of tumor recurrence after treatment (Miyazaki et al, 2020). It is urgent to improve the sensitivity of glioma to TMZ

Methods

Results

Conclusion