17β‐Estradiol Induces Temozolomide Resistance through Redox Optimization in Glioblastoma

Abstract

Glioblastoma is the most fatal cancer of all brain tumors, and the standard treatment of glioblastoma patients is surgical tumor resection followed by radiotherapy and temozolomide (TMZ)‐mediated chemotherapy. According to the TCGA databases, female patients exhibit poorer prognosis compared with male patients, suggesting that the gender‐specific hormone plays an important role in glioblastoma malignancy. In addition to acting as a female sex hormone, 17β‐estradiol is an important neuro‐steroid for brain health, including learning and memory. Numerous studies indicate that 17β‐estradiol aggressively participates in the pathogenesis of endocrine‐related cancers, such as breast and prostate cancers. However, the role of 17β‐estradiol is studied poorly in glioblastoma which exhibits strong neurosteroidogenesis. In this study, we attempt to elucidate whether 17β‐estradiol is involved in acquired resistance of glioblastoma to TMZ. Herein, we found that the level of 17β‐estradiol is significantly increased in TMZ‐resistant glioblastoma. Moreover, 17β‐estradiol attenuated TMZ‐induced cell death in A172 and U87MG cells. To dissect mechanisms underlying 17β‐estradiol‐induced resistance, we investigated whether 17β‐estradiol affected TMZ‐induced DNA damage and ROS production. Particularly, 17β‐estradiol significantly attenuated TMZ‐induced ROS production and hydrogen peroxide accumulation without affecting DNA damage. Further, 17β‐estradiol obviously prevented TMZ‐induced mitochondria dysfunctions characterized by the elevation of mitochondrial ROS and the reduction of ATP production. In addition, 17β‐estradiol treatment increased expression of multiple anti‐oxidant proteins, including superoxide dismutase (SOD) 1, SOD2, catalase (CAT), glutathione reductase, and nuclear factor erythroid 2 like 2. In particular, 17β‐estradiol promoted degradation of hydrogen peroxide through activating CAT, not through glutathione‐ and redox‐in‐mediated catabolic pathways. Based on these findings, we conclude that 17β‐estradiol counteracts TMZ‐induced oxidative stress through enhancing mitochondrial activity and CAT, leading to TMZ resistance.Support or Funding InformationTsung‐I Hsu