title: Latent membrane protein 1 mediates the resistance of nasopharyngeal             carcinoma cells to TRAIL-induced apoptosis by activation of the PI3K/Akt signaling             pathway.
abstract: The 5-year survival rate of nasopharyngeal carcinoma (NPC) is still disappointing             despite the much improved technologies in its treatment. Tumor necrosis factor-related             apoptosis inducing ligand (TRAIL) can selectively induce apoptosis in most tumor             cells while sparing normal cells. However, its potential in the treatment of NPC             has been limited by the eventual emergence of drug resistance. Latent membrane             protein 1 (LMP1) is a major oncogene of the human DNA tumor virus Epstein-Barr             virus (EBV) and is associated with the development of NPC and the emergence of             chemo-resistance in NPC. In this study, we investigated the potential role of             LMP1 in TRAIL resistance in CNE-1 NPC cells. Results show that overexpression             of LMP1 could induce TRAIL resistance in NPC cells without influencing death receptors.             The LMP1-induced TRAIL resistance is associated with increased expression of FLIP             and elevated cleavage of caspase-8 without altering the TRAIL-mediated mitochondrial             events and Bid cleavage. Knockdown of the FLIP gene with siRNA prevented the LMP1-induced             TRAIL resistance. Furthermore, we found that overexpression of LMP1 activated             Akt. Inhibition of Akt with LY294002 completely prevented the LMP1-induced FLIP             expression and TRAIL resistance. Together, these results show that LMP1 can inhibit             the TRAIL-mediated apoptosis through activation of PI3K/Akt and expression of             FLIP in CNE-1 NPC cells, and may provide new methods to prevent and reverse drug             resistance in NPC.
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, PR China.
authors.forename: Shi-Sheng
authors.initials: SS
authors.lastname: Li
authors.forename: Shu
authors.initials: S
authors.lastname: Yang
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Yang
authors.forename: Qing-Lai
authors.initials: QL
authors.lastname: Tang
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D053218:Receptors, Death Domain / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014763:Viral Matrix Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; D014763:Viral Matrix Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C505530:CASP8 protein, human; D053181:Caspase 8