title: The suppression of aurora-A/STK15/BTAK expression enhances chemosensitivity to docetaxel in human esophageal squamous cell carcinoma.
abstract: OBJECTIVE
  We previously reported that the expression of Aurora-A was frequently up-regulated in human esophageal squamous cell carcinoma (ESCC) tissues as well as cell lines and the up-regulation contributed to a poor prognosis. In this study, we assessed the possibility of Aurora-A suppression as a therapeutic target for ESCC using ESCC cell lines.
  
  
  METHODS
  We established subclones using vector-based short hairpin RNA (shRNA). Then, we investigated the effect of Aurora-A suppression on proliferation and cell cycle changes in vitro. Next, chemosensitivity against docetaxel was investigated by tetrazolium salt-based proliferation assay (WST assay) and cell number determinations, and furthermore, the type of cell death induced by docetaxel was analyzed by flow cytometry. Finally, to examine the effect of Aurora-A shRNA on proliferation and chemosensitivity against docetaxel in vivo, a s.c. tumor formation assay in nude mice was done.
  
  
  RESULTS
  We established two genetically different stable cell lines (510 A and 1440 A) in which levels of Aurora-A were reduced. Cell growth was inhibited by 38.7% in 510 A and by 24.3% in 1440 A in vitro compared with empty vector-transfected controls (510 m and 1440 m), and this growth inhibition was mediated through G(2)-M arrest as confirmed by flow cytometry. Next, in a WST assay, the IC(50) for Aurora-A shRNA-transfected cells was lower than that of empty vector-transfected cells (510 A, 2.7 x 10(-7) mol/L; 510 m, 4.8 x 10(-7) mol/L; 1440 A, 2.6 x 10(-7) mol/L; 1440 m, 4.9 x 10(-7) mol/L). In addition, 0.3 nmol/L docetaxel induced a notable level of apoptosis in Aurora-A shRNA-transfected cells compared with empty vector-transfected cells. In the assay of s.c. tumors in nude mice, tumor growth in 510 A was inhibited by 36.1% compared with that in 510 m, and in tumors treated with docetaxel, the suppression of Aurora-A resulted in 44.0% tumor growth suppression in vivo.
  
  
  CONCLUSIONS
  These results indicated that Aurora-A might play an important role in chemosensitivity to docetaxel, and the suppression of its expression might be a potential therapeutic target for ESCC.
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Tanaka
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ito
authors.forename: Kan
authors.initials: K
authors.lastname: Kondo
authors.forename: Motoshige
authors.initials: M
authors.lastname: Higashiyama
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tsunoda
authors.forename: Cristian
authors.initials: C
authors.lastname: Ortiz
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Sakai
authors.forename: Johji
authors.initials: J
authors.lastname: Inazawa
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimada
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D064096:Aurora Kinase A; D064127:Aurora Kinases; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D043823:Taxoids / Q000378:metabolism / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D043823:Taxoids; D000077143:Docetaxel; C576917:AURKA protein, human; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases