title: Zinc suppresses stem cell properties of lung cancer cells through protein kinase C-mediated β-catenin degradation.
abstract: Highly tumorigenic cancer stem cells (CSCs) residing in most cancers are responsible for cancer progression and treatment failure. Zinc is an element regulator of several cell functions; however, its role in regulation of stem cell program in lung cancer has not been demonstrated. The present study reveals for the first time that zinc can suppress stem cell properties of lung cancer cells. Such findings were proved in different lung cancer cell lines (H460, H23, and H292) and it was found that CSC markers (CD133 and ALDH1A1), stem cell-associated transcription factors (Oct4, Nanog, and Sox-2), and the ability to form tumor spheroid were dramatically suppressed by zinc treatments. Zinc was found to activate protein kinase C-α (PKCα) that further phosphorylated and mediated β-catenin degradation through the ubiquitin-proteasomal pathway. Zinc was found to increase the β-catenin-ubiquitin complex, which can be inhibited by a specific PKC inhibitor, bisindolylmaleimide I. Using specific reactive oxygen species detection and antioxidants, we have demonstrated that superoxide anions generated by zinc are a key upstream mechanism for PKCα activation leading to the subsequent suppression of stem cell features of lung cancer. Zinc increased cellular superoxide anions and the addition of superoxide anion scavenger prevented the activation of PKCα and β-catenin degradation. These findings indicate a novel role for zinc regulation in the PKCα/β-catenin pathway and explain an important mechanism for controlling of stem cell program in lung cancer cells.
authors.affiliation: Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand; and.|Cell-Based Drug and Health Products Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Chuanpit
authors.initials: C
authors.lastname: Ninsontia
authors.affiliation: Cell-Based Drug and Health Products Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Preeyaporn Plaimee
authors.initials: PP
authors.lastname: Phiboonchaiyanan
authors.affiliation: Cell-Based Drug and Health Products Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Chayanin
authors.initials: C
authors.lastname: Kiratipaiboon
authors.affiliation: Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand; and pithi_chan@yahoo.com.|Cell-Based Drug and Health Products Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Pithi
authors.initials: P
authors.lastname: Chanvorachote
mesh_terms: D063646:Carcinogenesis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015032:Zinc / Q000008:administration & dosage*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051176:beta Catenin; D011493:Protein Kinase C; D015032:Zinc
keywords: lung cancer; metastasis; stem cell; superoxide anion; zinc; β-catenin