AR ubiquitination induced by the curcumin analog suppresses growth of temozolomide-resistant glioblastoma through disrupting GPX4-Mediated redox homeostasis

• Published in: Redox biology Vol. 30; p. 101413
• Main Authors: Chen, Tzu-Chi, Chuang, Jian-Ying, Ko, Chiung-Yuan, Kao, Tzu-Jen, Yang, Pei-Yu, Yu, Chun-Hui, Liu, Ming-Sheng, Hu, Siou-Lian, Tsai, Yu-Ting, Chan, Hardy, Chang, Wen-Chang, Hsu, Tsung-I.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-02-2020; Elsevier
• Subjects: ALZ003; Animals; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Cell Proliferation - drug effects; Curcumin - analogs & derivatives; Drug Resistance, Neoplasm - drug effects; F-Box Proteins - metabolism; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - metabolism; GPX4; Humans; Male; Mice; Phospholipid Hydroperoxide Glutathione Peroxidase - genetics; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Primary Cell Culture; Proteolysis; Receptors, Androgen - metabolism; Research Paper; Tumor Cells, Cultured; Tumor Microenvironment - drug effects; Ubiquitination; Xenograft Model Antitumor Assays; AR; GPX4; ALZ003; Glioblastoma
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2019.101413

Drug resistance is the main obstacle in the improvement of chemotherapeutic efficacy in glioblastoma. Previously, we showed that dehydroepiandrosterone (DHEA), one kind of androgen/neurosteroid, potentiates glioblastoma to acquire resistance through attenuating DNA damage. Androgen receptor (AR) activated by DHEA or other types of androgen was reported to promote drug resistance in prostate cancer. However, in DHEA-enriched microenvironment, the role of AR in acquiring resistance of glioblastoma remains unknown. In this study, we found that AR expression is significantly correlated with poor prognosis, and AR obviously induced the resistance to temozolomide (TMZ) treatment. Herein, we observed that ALZ003, a curcumin analog, induces FBXL2-mediated AR ubiquitination, leading to degradation. Importantly, ALZ003 significantly inhibited the survival of TMZ-sensitive and –resistant glioblastoma in vitro and in vivo. The accumulation of reactive oxygen species (ROS), lipid peroxidation and suppression of glutathione peroxidase (GPX) 4, which are characteristics of ferroptosis, were observed in glioblastoma cell after treatment of ALZ003. Furthermore, overexpression of AR prevented ferroptosis in the presence of GPX4. To evaluate the therapeutic effect in vivo, we transplanted TMZ-sensitive or -resistant U87MG cells into mouse brain followed by intravenous administration with ALZ003. In addition to inhibiting the growth of glioblastoma, ALZ003 significantly extended the survival period of transplanted mice, and significantly decreased AR expression in the tumor area. Taken together, AR potentiates TMZ resistance for glioblastoma, and ALZ003-mediated AR ubiquitination might open a new insight into therapeutic strategy for TMZ resistant glioblastoma.
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•ALZ003, the curcumin analog, inhibits TMZ–resistant glioblastoma.•ALZ003 induces AR degradation through FBXL2-mediated ubiquitination.•ALZ003 induces ferroptosis through blocking AR-mediated GPX4 expression.•ALZ003 increases ROS and lipid peroxidation through reducing GPX4 expression.