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.
Original language | English |
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Article number | 473 |
Journal | International journal of molecular sciences |
Volume | 20 |
Issue number | 3 |
DOIs | |
Publication status | Published - 2019 Feb 1 |
Keywords
- Apoptosis
- Autophagy
- Glioblastoma
- P62
- Thioridazine
- Wnt/β-catenin
- Glioma/metabolism
- Catenins/metabolism
- Humans
- Apoptosis/drug effects
- Autophagy/drug effects
- Cell Survival/drug effects
- Wnt Signaling Pathway/drug effects
- Cell Cycle/drug effects
- Blotting, Western
- Thioridazine/pharmacology
- Receptors, G-Protein-Coupled/metabolism
- Cell Line, Tumor
- Beclin-1/metabolism
ASJC Scopus subject areas
- Molecular Biology
- Spectroscopy
- Catalysis
- Inorganic Chemistry
- Computer Science Applications
- Physical and Theoretical Chemistry
- Organic Chemistry