title: Silencing of LMP1 induces cell cycle arrest and enhances chemosensitivity through inhibition of AKT signaling pathway in EBV-positive nasopharyngeal carcinoma cells.
abstract: The latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is closely associated with nasopharyngeal carcinoma (NPC). In this study, we investigated that the effect of silencing LMP1 on cell cycle distribution and chemosensitivity in EBV-positive naso-pharyngeal carcinoma C666-1 cells. Silencing of LMP1 by specific siRNA induced G1 arrest in C666-1 cells. The protein expression of CDK4 and cyclin D1 decreased and P27 was upregulated following LMP1 knockdown. Phosphorylation of AKT and its downstream targets IkappaB, FKHR was inhibited by LMP1 siRNA. The chemosensitivity of C666-1 cells to bleomycin and cisplatin was enhanced by siRNA targeting LMP1. The cells treated with LMP1 siRNA showed enhanced cleavage of the effector caspase3 and PARP, and Bax had the tendency to exhibit higher expression. Also, cotransfection of constitutive active AKT plasmid with LMP-1 siRNA plasmid abrogates sensitivity of C666-1 to bleomycin and cisplatin. It is reported for the first time that AKT signaling pathway was directly involved in the effects induced by siRNA targeting LMP1. Our findings confirm LMP1 as a rational therapeutic target in NPC.
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Mei
authors.forename: Jun-Min
authors.initials: JM
authors.lastname: Zhou
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.forename: Rong
authors.initials: R
authors.lastname: Deng
authors.forename: Gong-Kan
authors.initials: GK
authors.lastname: Feng
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zhu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects; D002472:Cell Transformation, Viral; D002945:Cisplatin / Q000494:pharmacology; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D020031:Epstein-Barr Virus Infections / Q000378:metabolism / Q000473:pathology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016193:G1 Phase; D019254:Genes, bcl-2; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D014162:Transfection; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; D018797:Cell Cycle Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D020672:I-kappa B Proteins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D014763:Viral Matrix Proteins; D051028:bcl-2-Associated X Protein; D001761:Bleomycin; D011065:Poly(ADP-ribose) Polymerases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D002945:Cisplatin