title: Caveolin-1 regulates lung cancer stem-like cell induction and p53 inactivation in carbon nanotube-driven tumorigenesis.
abstract: Cancer stem cells (CSCs) may represent targets for carcinogenic initiation by chemical and environmental agents. Recent studies have raised a concern over the potential carcinogenicity of carbon nanotubes (CNTs), one of the most commonly used engineered nanomaterials with asbestos-like properties. Here, we show that chronic (6-month) exposure of human lung epithelial cells to single-walled (SW) CNTs at the workplace-relevant concentration induced an emergence of lung CSCs, as indicated by the induction of CSC tumor spheres and side population (SP). These CSCs, which were found to overexpress tumor promoter caveolin-1 (Cav-1), displayed aggressive cancer phenotypes of apoptosis resistance and enhanced cell invasion and migration compared with their non-CSC counterpart. Using gene manipulation strategies, we reveal for the first time that Cav-1 plays an essential role in CSC regulation and aggressiveness of SWCNT-transformed cells partly through p53 dysregulation, consistent with their suggested role by microarray and gene ontology analysis. Cav-1 not only promoted tumorigenesis in a xenograft mouse model but also metastasis of the transformed cells to neighboring tissues. Since CSCs are crucial to the initiation and early development of carcinogenesis, our findings on CSC induction by SWCNTs and Cav-1 could aid in the early detection and risk assessment of the disease.
authors.affiliation: Pharmaceutical and Pharmacological Sciences Program; Mary Babb Randolph Cancer Center, West Virginia University, WV 26506, USA.
authors.forename: Sudjit
authors.initials: S
authors.lastname: Luanpitpong
authors.forename: Liying
authors.initials: L
authors.lastname: Wang
authors.forename: Todd A
authors.initials: TA
authors.lastname: Stueckle
authors.forename: William
authors.initials: W
authors.lastname: Tse
authors.forename: Yi Charlie
authors.initials: YC
authors.lastname: Chen
authors.forename: Yon
authors.initials: Y
authors.lastname: Rojanasakul
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced*; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D064593:Heterografts; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D037742:Nanotubes, Carbon / Q000633:toxicity*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051242:Caveolin 1; D037742:Nanotubes, Carbon; D016159:Tumor Suppressor Protein p53