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

2 Citations (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

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Keywords

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

ASJC Scopus subject areas

  • Toxicology

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