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Thioridazine Enhances P62-Mediated Autophagy and Apoptosis Through Wnt/β-Catenin Signaling Pathway in Glioma Cells

Authors :
Yun Ling Lai
Hui Wen Cheng
Chen Yen Lin
Yi Ren Hong
Huey Jiun Ko
Chi Ying F. Huang
Tai Shan Cheng
Jiin Tsuey Cheng
Shean Jaw Chiou
Chihuei Wang
Joon Khim Loh
Cheng Wei Chu
Yu Hsin Liang
Chia Hua Chou
Chun Li Su
Source :
International Journal of Molecular Sciences, International Journal of Molecular Sciences, Vol 20, Iss 3, p 473 (2019)
Publication Year :
2019
Publisher :
MDPI, 2019.

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.

Details

Language :
English
ISSN :
14220067
Volume :
20
Issue :
3
Database :
OpenAIRE
Journal :
International Journal of Molecular Sciences
Accession number :
edsair.doi.dedup.....1c7cdc90db8636e94a5f5806d944bfeb