title: Carbon nanotubes induce apoptosis resistance of human lung epithelial cells through FLICE-inhibitory protein.
abstract: Chronic exposure to single-walled carbon nanotubes (SWCNT) has been reported to induce apoptosis resistance of human lung epithelial cells. As resistance to apoptosis is a foundation of neoplastic transformation and cancer development, we evaluated the apoptosis resistance characteristic of the exposed lung cells to understand the pathogenesis mechanism. Passage control and SWCNT-transformed human lung epithelial cells were treated with known inducers of apoptosis via the intrinsic (antimycin A and CDDP) or extrinsic (FasL and TNF-α) pathway and analyzed for apoptosis by DNA fragmentation, annexin-V expression, and caspase activation assays. Whole-genome microarray was performed to aid the analysis of apoptotic gene signaling network. The SWCNT-transformed cells exhibited defective death receptor pathway in association with cellular FLICE-inhibitory protein (c-FLIP) overexpression. Knockdown or chemical inhibition of c-FLIP abrogated the apoptosis resistance of SWCNT-transformed cells. Whole-genome expression signature analysis confirmed these findings. This study is the first to demonstrate carbon nanotube-induced defective death receptor pathway and the role of c-FLIP in the process.
authors.affiliation: *Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia 26506, Department of Pharmacology and Physiology, Chulalongkorn University, Bangkok, Thailand, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506, Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, Allergy and Clinical Immunology Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, and National Nanotechnology Center, Pathumthani, Thailand *Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia 26506, Department of Pharmacology and Physiology, Chulalongkorn University, Bangkok, Thailand, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506, Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, Allergy and Clinical Immunology Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, and National Nanotechnology Center, Pathumthani, Thailand.
authors.forename: Varisa
authors.initials: V
authors.lastname: Pongrakhananon
authors.affiliation: *Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia 26506, Department of Pharmacology and Physiology, Chulalongkorn University, Bangkok, Thailand, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506, Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, Allergy and Clinical Immunology Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, and National Nanotechnology Center, Pathumthani, Thailand *Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia 26506, Department of Pharmacology and Physiology, Chulalongkorn University, Bangkok, Thailand, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506, Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, Allergy and Clinical Immunology Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, and National Nanotechnology Center, Pathumthani, Thailand *Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia 26506, Department of Pharmacology and Physiology, Chulalongkorn University, Bangkok, Thailand, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506, Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, Allergy and Clinical Immunology Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, and National Nanotechnology Center, Pathumthani, Thailand.
authors.forename: Sudjit
authors.initials: S
authors.lastname: Luanpitpong
authors.affiliation: *Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia 26506, Department of Pharmacology and Physiology, Chulalongkorn University, Bangkok, Thailand, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506, Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, Allergy and Clinical Immunology Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, and National Nanotechnology Center, Pathumthani, Thailand *Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia 26506, Department of Pharmacology and Physiology, Chulalongkorn University, Bangkok, Thailand, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506, Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, Allergy and Clinical Immunology Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, and National Nanotechnology Center, Pathumthani, Thailand.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Stueckle
authors.affiliation: *Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia 26506, Department of Pharmacology and Physiology, Chulalongkorn University, Bangkok, Thailand, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506, Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, Allergy and Clinical Immunology Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, and National Nanotechnology Center, Pathumthani, Thailand.
authors.forename: Liying
authors.initials: L
authors.lastname: Wang
authors.affiliation: *Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia 26506, Department of Pharmacology and Physiology, Chulalongkorn University, Bangkok, Thailand, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506, Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, Allergy and Clinical Immunology Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, and National Nanotechnology Center, Pathumthani, Thailand.
authors.forename: Ubonthip
authors.initials: U
authors.lastname: Nimmannit
authors.affiliation: *Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia 26506, Department of Pharmacology and Physiology, Chulalongkorn University, Bangkok, Thailand, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506, Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, Allergy and Clinical Immunology Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, and National Nanotechnology Center, Pathumthani, Thailand *Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia 26506, Department of Pharmacology and Physiology, Chulalongkorn University, Bangkok, Thailand, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506, Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, Allergy and Clinical Immunology Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, and National Nanotechnology Center, Pathumthani, Thailand yrojan@hsc.wvu.edu.
authors.forename: Yon
authors.initials: Y
authors.lastname: Rojanasakul
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018929:Cell Culture Techniques; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D037742:Nanotubes, Carbon / Q000633:toxicity*; D053218:Receptors, Death Domain / Q000378:metabolism
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D037742:Nanotubes, Carbon; D053218:Receptors, Death Domain
keywords: apoptosis; c-FLIP; carbon nanotubes; death receptor; lung