Down‐regulation of β‐catenin and the associated migration ability by Taiwanin C in arecoline and 4‐NQO‐induced oral cancer cells via GSK‐3β activation

• Published in: Molecular carcinogenesis 2017-03, Vol.56 (3), p.1055-1067
• Main Authors: Hsieh, Cheng‐Hong, Hsu, Hsi‐Hsien, Shibu, Marthandam Asokan, Day, Cecilia‐Hsuan, Bau, Da‐Tian, Ho, Chih‐Chu, Lin, Yueh‐Min, Chen, Ming‐Cheng, Wang, Shu‐Huai, Huang, Chih‐Yang
• Format: Article
• Language: English
• Subjects: 4-Nitroquinoline-1-oxide - adverse effects; Animals; Arecoline - adverse effects; beta Catenin - metabolism; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Down-Regulation; Enzyme Activation; Gene Expression Regulation, Neoplastic - drug effects; Glycogen Synthase Kinase 3 beta - metabolism; Humans; Lactones - administration & dosage; Lactones - pharmacology; Lignans - administration & dosage; Lignans - pharmacology; metastasis; Mice; Mouth Neoplasms - chemically induced; Mouth Neoplasms - drug therapy; Mouth Neoplasms - metabolism; oral cancer; Signal Transduction - drug effects; Taiwania cryptomerioides; Taiwanin C; Xenograft Model Antitumor Assays
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.22570

Cancer is one of the leading causes of death worldwide, and oral squamous cell carcinoma (OSCC) accounts for almost a sixth of all reported cancers. Arecoline, from areca nut is known to enhance carcinogenesis in oral squamous cells. The objective of this study is to determine the effect of Taiwanin C, from Taiwania cryptomerioides Hayata against Arecoline‐associated carcinogenesis. An OSCC model was created in C57BL/6J Narl mice by administrating 0.5 mg mL−1 arecoline with 0.2 mg mL−1 4‐NQO carcinogen for 8 and 28 wk to mimic the etiology of oral cancer patients in Asia. Mice were sacrificed and two cell lines, T28 from the tumor and N28 cancerous cell line from the surrounding non tumor area, were established. Taiwanin C showed effective anti‐tumor activity in nude mice models. Taiwanin C significantly inhibited the cell viability of T28 cells in a dose dependent manner, but did not inflict any effect on N28 normal cells. Taiwanin C treatment inhibited the migration ability of T28 cells in a dose dependent manner as determined by wound healing and migration assays. Taiwanin C also reduced the levels of β‐catenin and its downstream metastatic proteins, Tbx3 and c‐Myc. Besides, Taiwanin C inhibited the nuclear accumulation of β‐catenin and induced β‐catenin degradation via proteasome‐mediated pathway. Moreover, Taiwanin C enhanced GSK‐3β and reduced the p‐ser9 GSK‐3β protein level to inactivate Wnt signaling. Taken together, Taiwanin C blocked the cell migration effects of T28 cells mediated through the activation of GSK‐3β to enhance protein degradation and reduce nuclear accumulation of β‐catenin. © 2016 Wiley Periodicals, Inc.