1. Thioridazine Enhances P62-Mediated Autophagy and Apoptosis Through Wnt/β-Catenin Signaling Pathway in Glioma Cells
- Author
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Cheng-Wei Chu, Huey-Jiun Ko, Chia-Hua Chou, Tai-Shan Cheng, Hui-Wen Cheng, Yu-Hsin Liang, Yun-Ling Lai, Chen-Yen Lin, Chihuei Wang, Joon-Khim Loh, Jiin-Tsuey Cheng, Shean-Jaw Chiou, Chun-Li Su, Chi-Ying F. Huang, and Yi-Ren Hong
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thioridazine ,glioblastoma ,Wnt/β-catenin ,P62 ,autophagy ,apoptosis ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Thioridazine (THD) is a common phenothiazine antipsychotic drug reported to suppress growth in several types of cancer cells. We previously showed that THD acts as an antiglioblastoma and anticancer stem-like cell agent. However, the signaling pathway underlying autophagy and apoptosis induction remains unclear. THD treatment significantly induced autophagy with upregulated AMPK activity and engendered cell death with increased sub-G1 in glioblastoma multiform (GBM) cell lines. Notably, through whole gene expression screening with THD treatment, frizzled (Fzd) proteins, a family of G-protein-coupled receptors, were found, suggesting the participation of Wnt/β-catenin signaling. After THD treatment, Fzd-1 and GSK3β-S9 phosphorylation (inactivated form) was reduced to promote β-catenin degradation, which attenuated P62 inhibition. The autophagy marker LC3-II markedly increased when P62 was released from β-catenin inhibition. Additionally, the P62-dependent caspase-8 activation that induced P53-independent apoptosis was confirmed by inhibiting T-cell factor/β-catenin and autophagy flux. Moreover, treatment with THD combined with temozolomide (TMZ) engendered increased LC3-II expression and caspase-3 activity, indicating promising drug synergism. In conclusion, THD induces autophagy in GBM cells by not only upregulating AMPK activity, but also enhancing P62-mediated autophagy and apoptosis through Wnt/β-catenin signaling. Therefore, THD is a potential alternative therapeutic agent for drug repositioning in GBM.
- Published
- 2019
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