title: 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.
abstract: 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-1arecoline with 0.2 mg mL-14-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-ser9GSK-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.
authors.affiliation: Department of Health and Nutritional Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Cheng-Hong
authors.initials: CH
authors.lastname: Hsieh
authors.affiliation: Division of Colorectal Surgery, Mackay Memorial Hospital, Taipei, Taiwan.|Mackay Medicine, Nursing and Management College, Taipei, Taiwan.
authors.forename: Hsi-Hsien
authors.initials: HH
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Marthandam Asokan
authors.initials: MA
authors.lastname: Shibu
authors.affiliation: Department of Nursing, Meiho University, Pingtung, Taiwan.
authors.forename: Cecilia-Hsuan
authors.initials: CH
authors.lastname: Day
authors.affiliation: Terry Fox Cancer Research Laboratory, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Da-Tian
authors.initials: DT
authors.lastname: Bau
authors.affiliation: HK. Zen Heart Group Biopharmaceutical Co., Limited, Wanchai, Hong Kong.|Zen Transmission Foundation of Medical Culture and Education, Taichung, Taiwan, ROC.
authors.forename: Chih-Chu
authors.initials: CC
authors.lastname: Ho
authors.affiliation: Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan.|Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management College, Taipei, Taiwan.
authors.forename: Yueh-Min
authors.initials: YM
authors.lastname: Lin
authors.affiliation: Division of Colorectal Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Ming-Cheng
authors.initials: MC
authors.lastname: Chen
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Shu-Huai
authors.initials: SH
authors.lastname: Wang
authors.affiliation: Department of Health and Nutritional Biotechnology, Asia University, Taichung, Taiwan.|Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.|Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000009:adverse effects; D000818:Animals; D001115:Arecoline / Q000009:adverse effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006801:Humans; D007783:Lactones / Q000008:administration & dosage* / Q000494:pharmacology; D017705:Lignans / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D007783:Lactones; D017705:Lignans; D051176:beta Catenin; C467766:taiwanin C; D001115:Arecoline; D015112:4-Nitroquinoline-1-oxide; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta
keywords: Taiwania cryptomerioides; Taiwanin C; metastasis; oral cancer