title: Prognostic significance of Bcl-xL expression and efficacy of Bcl-xL targeting therapy in urothelial carcinoma.
abstract: BACKGROUND
  Bcl-xL has an important role in the control of cell death through its inhibition of apoptosis. The aim of this study was to investigate the clinicopathological significance of Bcl-xL in upper urinary tract urothelial carcinoma (UTUC) and the therapeutic effect of targeting Bcl-xL protein in urothelial carcinoma (UC) cells.
  
  
  METHODS
  We evaluated the immunohistochemical expression of Bcl-xL in 175 UTUC patients to determine the clinical role of Bcl-xL expression in clinical outcome. We used bafilomycin A1 (BMA) as a specific inhibitor of Bcl-xL to examine the biological effects in UC cells in vitro and in vivo.
  
  
  RESULTS
  Immunohistochemical analysis of Bcl-xL expression revealed that patients with a high Bcl-xL score had a significantly lower 5-year cancer-specific survival (CSS) rate (53.2%) than those with a low Bcl-xL score (77.2%) (P=0.0011). Multivariate analysis indicated that a high Bcl-xL score was an independent prognostic factor of CSS (P=0.023). BMA inhibited UMUC-3 cell proliferation in vitro by induction of apoptosis. Treatment with BMA significantly inhibited tumour growth in UMUC-3 tumours in this mouse xenograft model accompanied by an elevated apoptosis induction.
  
  
  CONCLUSIONS
  Bcl-xL appears to be a significant molecular marker for the prognosis of UTUCs. Targeting Bcl-xL may be a promising therapeutic strategy for patients with UC.
authors.affiliation: Department of Urology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Yoshimine
authors.forename: E
authors.initials: E
authors.lastname: Kikuchi
authors.forename: T
authors.initials: T
authors.lastname: Kosaka
authors.forename: S
authors.initials: S
authors.lastname: Mikami
authors.forename: A
authors.initials: A
authors.lastname: Miyajima
authors.forename: Y
authors.initials: Y
authors.lastname: Okada
authors.forename: M
authors.initials: M
authors.lastname: Oya
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018942:Macrolides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D011379:Prognosis; D012189:Retrospective Studies; D014516:Ureteral Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: C494811:BCL2L1 protein, human; D018942:Macrolides; D051020:bcl-X Protein; C057620:bafilomycin A