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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)65-72
Number of pages8
JournalToxicology
Volume410
DOIs
Publication statusPublished - Dec 1 2018

Fingerprint

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

Keywords

  • Paraquat
  • Parkinson's disease
  • WNT/β-CATENIN

ASJC Scopus subject areas

  • Toxicology

Cite this

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.

In: Toxicology, Vol. 410, 01.12.2018, p. 65-72.

Research output: Contribution to journalArticle

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. In: Toxicology. 2018 ; Vol. 410. pp. 65-72.
@article{1dc65ba7ccc844d6b1ba1783e25da682,
title = "LGK974, a PORCUPINE inhibitor, mitigates cytotoxicity in an in vitro model of Parkinson's disease by interfering with the WNT/β-CATENIN pathway",
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.",
keywords = "Paraquat, Parkinson's disease, WNT/β-CATENIN",
author = "Yang, {Jung Mou} and Huang, {Huei Mei} and Cheng, {Jing Jy} and Huang, {Chuen Lin} and Lee, {Yi Chao} and Chiou, {Chun Tang} and Huang, {Hung Tse} and Huang, {Nai Kuei} and Yang, {Ying Chen}",
year = "2018",
month = "12",
day = "1",
doi = "10.1016/j.tox.2018.09.003",
language = "English",
volume = "410",
pages = "65--72",
journal = "Toxicology",
issn = "0300-483X",
publisher = "Elsevier Ireland Ltd",

}

TY - JOUR

T1 - LGK974, a PORCUPINE inhibitor, mitigates cytotoxicity in an in vitro model of Parkinson's disease by interfering with the WNT/β-CATENIN pathway

AU - Yang, Jung Mou

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

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

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.

KW - Paraquat

KW - Parkinson's disease

KW - WNT/β-CATENIN

UR - http://www.scopus.com/inward/record.url?scp=85053406446&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85053406446&partnerID=8YFLogxK

U2 - 10.1016/j.tox.2018.09.003

DO - 10.1016/j.tox.2018.09.003

M3 - Article

AN - SCOPUS:85053406446

VL - 410

SP - 65

EP - 72

JO - Toxicology

JF - Toxicology

SN - 0300-483X

ER -