title: Antibiotic drug rifabutin is effective against lung cancer cells by targeting the eIF4E-β-catenin axis.
abstract: The essential roles of overexpression of eukaryotic translation initiation factor 4E (eIF4E) and aberrant activation of β-catenin in lung cancer development have been recently identified. However, whether there is a direct connection between eIF4E overexpression and β-catenin activation in lung cancer cells is unknown. In this study, we show that antibiotic drug rifabutin targets human lung cancer cells via inhibition of eIF4E-β-catenin axis. Rifabutin is effectively against lung cancer cells in in vitro cultured cells and in vivo xenograft mouse model through inhibiting proliferation and inducing apoptosis. Mechanistically, eIF4E regulates β-catenin activity in lung cancer cells as shown by the increased β-catenin phosphorylation and activity in cells overexpressing eIF4E, and furthermore that the regulation is dependent on phosphorylation at S209. Rifabutin suppresses eIF4E phosphorylation, leads to decreased β-catenin phosphorylation and its subsequent transcriptional activities. Depletion of eIF4E abolishes the inhibitory effects of rifabutin on β-catenin activities and overexpression of β-catenin reverses the inhibitory effects of rifabutin on cell growth and survival, further confirming that rifabutin acts on lung cancer cells via targeting eIF4E- β-catenin axis. Our findings identify the eIF4E- β-catenin axis as a critical regulator of lung cancer cell growth and survival, and suggest that its pharmacological inhibition may be therapeutically useful in lung cancer.
authors.affiliation: Department of Respiratory Medicine, Hainan General Hospital, Hainan Province, People's Republic of China.
authors.forename: Ji
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Respiratory Medicine, Hainan General Hospital, Hainan Province, People's Republic of China.
authors.forename: Yijiang
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Equipment Division, Hainan General Hospital, Hainan Province, People's Republic of China.
authors.forename: Yunsuo
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Respiratory Medicine, Hainan General Hospital, Hainan Province, People's Republic of China.
authors.forename: Haihong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Respiratory Medicine, Hainan General Hospital, Hainan Province, People's Republic of China.
authors.forename: Wen
authors.initials: W
authors.lastname: Dong
authors.affiliation: Department of Ophthalmology, Hainan Eye Hospital, ZhongShan Ophthalmic Centre, Sun Yat-Sen University, Hainan Province, People's Republic of China. Electronic address: echoliun@hotmail.com.
authors.forename: Lina
authors.initials: L
authors.lastname: Liu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D058492:Drug Repositioning / Q000379:methods*; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D017828:Rifabutin / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; C495267:CTNNB1 protein, mouse; D039561:Eukaryotic Initiation Factor-4E; D051176:beta Catenin; C000601282:eIF4E protein, mouse; D017828:Rifabutin
keywords: Drug repositioning; Lung cancer; Rifabutin; eIF4E; β-catenin