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 |
|---|---|
| Article number | 473 |
| Journal | International journal of molecular sciences |
| Volume | 20 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2019 Feb 1 |
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Keywords
- Apoptosis
- Autophagy
- Glioblastoma
- P62
- Thioridazine
- Wnt/β-catenin
ASJC Scopus subject areas
- Catalysis
- Molecular Biology
- Spectroscopy
- Computer Science Applications
- Physical and Theoretical Chemistry
- Organic Chemistry
- Inorganic Chemistry
Cite this
Thioridazine enhances p62-mediated autophagy and apoptosis through Wnt/β-catenin signaling pathway in glioma cells. / Chu, Cheng Wei; Ko, Huey Jiun; Chou, Chia Hua; Cheng, Tai Shan; Cheng, Hui Wen; Liang, Yu Hsin; Lai, Yun Ling; Lin, Chen Yen; Wang, Chihuei; Loh, Joon Khim; Cheng, Jiin Tsuey; Chiou, Shean Jaw; Su, Chun Li; Huang, Chi Ying F.; Hong, Yi Ren.
In: International journal of molecular sciences, Vol. 20, No. 3, 473, 01.02.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Thioridazine enhances p62-mediated autophagy and apoptosis through Wnt/β-catenin signaling pathway in glioma cells
AU - Chu, Cheng Wei
AU - Ko, Huey Jiun
AU - Chou, Chia Hua
AU - Cheng, Tai Shan
AU - Cheng, Hui Wen
AU - Liang, Yu Hsin
AU - Lai, Yun Ling
AU - Lin, Chen Yen
AU - Wang, Chihuei
AU - Loh, Joon Khim
AU - Cheng, Jiin Tsuey
AU - Chiou, Shean Jaw
AU - Su, Chun Li
AU - Huang, Chi Ying F.
AU - Hong, Yi Ren
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Autophagy
KW - Glioblastoma
KW - P62
KW - Thioridazine
KW - Wnt/β-catenin
UR - http://www.scopus.com/inward/record.url?scp=85060514728&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85060514728&partnerID=8YFLogxK
U2 - 10.3390/ijms20030473
DO - 10.3390/ijms20030473
M3 - Article
C2 - 30678307
AN - SCOPUS:85060514728
VL - 20
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 3
M1 - 473
ER -