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

Author:
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
Source:
Toxicology 2018 v.410 pp. 65-72
ISSN:
0300-483X
Subject:
Parkinson disease, agonists, apoptosis, beta catenin, brain, clinical trials, cytotoxicity, etiology, glycogen synthase kinases, humans, mitochondria, models, neoplasms, neurogenesis, neurons, paraquat, patients, therapeutics
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.
Agid:
6144668