LGK974, a PORCUPINE inhibitor, mitigates cytotoxicity in an in vitro model of Parkinson's disease by interfering with the WNT/β-CATENIN pathway

Jung Mou Yang, Huei Mei Huang, Jing Jy Cheng, Chuen Lin Huang, Yi Chao Lee, Chun Tang Chiou, Hung Tse Huang, Nai Kuei Huang, Ying Chen Yang

研究成果: 雜誌貢獻文章

1 引文 (Scopus)

摘要

Paraquat (PQ) as an herbicide has been demonstrated to impair dopaminergic (DAergic) neurons and highly correlate with the etiology of Parkinson's disease (PD). WNT/β-CATENIN signaling is known for the specification and neurogenesis of midbrain DAergic neurons and implicated as a therapeutic target in treating many diseases, such as cancer and degenerative diseases. LGK974, a WNT pathway inhibitor, is currently under clinical trial for patients with malignancies. Since the exact role of WNT/β-CATENIN signaling in mediating PD is undetermined, LGK974 was used to examine its effect on the PQ-induced cell model of PD. LGK974 attenuated PQ-induced apoptosis and released mitochondrial pro-poptotic molecules in human neuroblastoma SH-SY5Y cell. PQ increased the levels of β-CATENIN, non-phosphorylated (Ser33/37/Thr41) β-CATENIN, and phosphorylated glycogen synthase kinase (GSK)-3α/β. PQ also increased the nuclear translocation of β-CATENIN, which can be attenuated by LKG974. Furthermore, LGK974 attenuated the PQ-induced release of mitochondrial proapoptotic factors and WNT agonist 1-induced cell death. Taken together, we have shown for the first time that LGK974 mediated through the WNT/β-CATENIN pathway to prevent PQ-induced cell death.
原文英語
頁(從 - 到)65-72
頁數8
期刊Toxicology
410
DOIs
出版狀態已發佈 - 十二月 1 2018

指紋

Paraquat
Cytotoxicity
Parkinson Disease
Dopaminergic Neurons
Cell death
Neurons
Cell Death
Glycogen Synthase Kinase 3
Neurogenesis
Herbicides
Mesencephalon
In Vitro Techniques
LGK974
Neuroblastoma
Neoplasms
Clinical Trials
Apoptosis
Specifications
Molecules

ASJC Scopus subject areas

  • Toxicology

引用此文

LGK974, a PORCUPINE inhibitor, mitigates cytotoxicity in an in vitro model of Parkinson's disease by interfering with the WNT/β-CATENIN pathway. / Yang, Jung Mou; Huang, Huei Mei; Cheng, Jing Jy; Huang, Chuen Lin; Lee, Yi Chao; Chiou, Chun Tang; Huang, Hung Tse; Huang, Nai Kuei; Yang, Ying Chen.

於: Toxicology, 卷 410, 01.12.2018, p. 65-72.

研究成果: 雜誌貢獻文章

Yang, Jung Mou ; Huang, Huei Mei ; Cheng, Jing Jy ; Huang, Chuen Lin ; Lee, Yi Chao ; Chiou, Chun Tang ; Huang, Hung Tse ; Huang, Nai Kuei ; Yang, Ying Chen. / LGK974, a PORCUPINE inhibitor, mitigates cytotoxicity in an in vitro model of Parkinson's disease by interfering with the WNT/β-CATENIN pathway. 於: Toxicology. 2018 ; 卷 410. 頁 65-72.
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abstract = "Paraquat (PQ) as an herbicide has been demonstrated to impair dopaminergic (DAergic) neurons and highly correlate with the etiology of Parkinson's disease (PD). WNT/β-CATENIN signaling is known for the specification and neurogenesis of midbrain DAergic neurons and implicated as a therapeutic target in treating many diseases, such as cancer and degenerative diseases. LGK974, a WNT pathway inhibitor, is currently under clinical trial for patients with malignancies. Since the exact role of WNT/β-CATENIN signaling in mediating PD is undetermined, LGK974 was used to examine its effect on the PQ-induced cell model of PD. LGK974 attenuated PQ-induced apoptosis and released mitochondrial pro-poptotic molecules in human neuroblastoma SH-SY5Y cell. PQ increased the levels of β-CATENIN, non-phosphorylated (Ser33/37/Thr41) β-CATENIN, and phosphorylated glycogen synthase kinase (GSK)-3α/β. PQ also increased the nuclear translocation of β-CATENIN, which can be attenuated by LKG974. Furthermore, LGK974 attenuated the PQ-induced release of mitochondrial proapoptotic factors and WNT agonist 1-induced cell death. Taken together, we have shown for the first time that LGK974 mediated through the WNT/β-CATENIN pathway to prevent PQ-induced cell death.",
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AU - Huang, Huei Mei

AU - Cheng, Jing Jy

AU - Huang, Chuen Lin

AU - Lee, Yi Chao

AU - Chiou, Chun Tang

AU - Huang, Hung Tse

AU - Huang, Nai Kuei

AU - Yang, Ying Chen

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AB - Paraquat (PQ) as an herbicide has been demonstrated to impair dopaminergic (DAergic) neurons and highly correlate with the etiology of Parkinson's disease (PD). WNT/β-CATENIN signaling is known for the specification and neurogenesis of midbrain DAergic neurons and implicated as a therapeutic target in treating many diseases, such as cancer and degenerative diseases. LGK974, a WNT pathway inhibitor, is currently under clinical trial for patients with malignancies. Since the exact role of WNT/β-CATENIN signaling in mediating PD is undetermined, LGK974 was used to examine its effect on the PQ-induced cell model of PD. LGK974 attenuated PQ-induced apoptosis and released mitochondrial pro-poptotic molecules in human neuroblastoma SH-SY5Y cell. PQ increased the levels of β-CATENIN, non-phosphorylated (Ser33/37/Thr41) β-CATENIN, and phosphorylated glycogen synthase kinase (GSK)-3α/β. PQ also increased the nuclear translocation of β-CATENIN, which can be attenuated by LKG974. Furthermore, LGK974 attenuated the PQ-induced release of mitochondrial proapoptotic factors and WNT agonist 1-induced cell death. Taken together, we have shown for the first time that LGK974 mediated through the WNT/β-CATENIN pathway to prevent PQ-induced cell death.

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