title: A novel Hsp90 inhibitor AT13387 induces senescence in EBV-positive nasopharyngeal carcinoma cells and suppresses tumor formation.
abstract: BACKGROUND
  Nasopharyngeal carcinoma (NPC) is an epithelial malignancy strongly associated with Epstein-Barr virus (EBV). AT13387 is a novel heat shock protein 90 (Hsp90) inhibitor, which inhibits the chaperone function of Hsp90 and reduces expression of Hsp90-dependent client oncoproteins. This study aimed to evaluate both the in vitro and in vivo antitumor effects of AT13387 in the EBV-positive NPC cell line C666-1.
  
  
  RESULTS
  Our results showed that AT13387 inhibited C666-1 cell growth and induced cellular senescence with the downregulation of multiple Hsp90 client oncoproteins EGFR, AKT, CDK4, and restored the protein expression of negative cell cycle regulator p27. We also studied the ability of AT13387 to restore p27 expression by downregulation of AKT and the p27 ubiquitin mediator, Skp2, using AKT inhibitor and Skp2 siRNA. In the functional study, AT13387 inhibited cell migration with downregulation of a cell migration regulator, HDAC6, and increased the acetylation and stabilization of α-tubulin. We also examined the effect of AT13387 on putative cancer stem cells (CSC) by 3-D tumor sphere formation assay. AT13387 effectively reduced both the number and size of C666-1 tumor spheres with decreased expression of NPC CSC-like markers CD44 and SOX2. In the in vivo study, AT13387 significantly suppressed tumor formation in C666-1 NPC xenografts.
  
  
  CONCLUSIONS
  AT13387 suppressed cell growth, cell migration, tumor sphere formation and induced cellular senescence on EBV-positive NPC cell line C666-1. Also, the antitumor effect of AT13387 was demonstrated in an in vivo model. This study provided experimental evidence for the preclinical value of using AT13387 as an effective antitumor agent in treatment of NPC.
authors.forename: King Chi
authors.initials: KC
authors.lastname: Chan
authors.forename: Choi Man
authors.initials: CM
authors.lastname: Ting
authors.forename: Pui Shan
authors.initials: PS
authors.lastname: Chan
authors.forename: Ming Chu
authors.initials: MC
authors.lastname: Lo
authors.forename: Kwok Wai
authors.initials: KW
authors.lastname: Lo
authors.forename: Jayne E
authors.initials: JE
authors.lastname: Curry
authors.forename: Tomoko
authors.initials: T
authors.lastname: Smyth
authors.forename: Anne Wing Mui
authors.initials: AW
authors.lastname: Lee
authors.forename: Wai Tong
authors.initials: WT
authors.lastname: Ng
authors.forename: George Sai Wah
authors.initials: GS
authors.lastname: Tsao
authors.forename: Ricky Ngok Shun
authors.initials: RN
authors.lastname: Wong
authors.forename: Maria Li
authors.initials: ML
authors.lastname: Lung
authors.affiliation: Department of Biology, Hong Kong Baptist University, Hong Kong, P,R, China. nkmak@hkbu.edu.hk.
authors.forename: Nai Ki
authors.initials: NK
authors.lastname: Mak
mesh_terms: D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002277:Carcinoma; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D020031:Epstein-Barr Virus Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D054833:Isoindoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C497483:CD44 protein, human; D018841:HSP90 Heat-Shock Proteins; D018960:Hyaluronan Receptors; D054833:Isoindoles; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D014404:Tubulin; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C552103:(2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone