title: Significance of 4E-binding protein 1 as a therapeutic target for invasive urothelial carcinoma of the bladder.
abstract: BACKGROUND
  To evaluate the expression of multiple molecular markers involved in the mammalian target of rapamycin (mTOR) signaling pathway in human muscle-invasive bladder cancer (BC) and to assess the therapeutic efficacies of mTOR inhibitors in human BC KoTCC-1 cells.
  
  
  METHODS
  Expression levels of 5 markers, including PTEN, phosphorylated (p)-Akt, p-mTOR, p-p70 ribosomal S6 kinase, and p-4E-binding protein 1 (4E-BP1), were measured in radical cystectomy specimens from 49 patients with muscle-invasive BC by immunohistochemical staining. We then analyzed the effects of treatment with temsirolimus or Ku-0063794, a dual inhibitor of mTOR complex 1 (C1) and mTOR complex 2 (C2), on changes in the growth and expression profiles of 5 mTOR-associated markers in KoTCC-1 cells.
  
  
  RESULTS
  During the follow-up period of this study, disease recurred in 27 patients (55.1%), and of several factors examined, the expression level of p-4E-BP1 in addition to the pathological T stage was independently related to recurrence-free survival on multivariate analysis. Although the growth of KoTCC-1 cells was inhibited by both temsirolimus and Ku-0063794 in dose-dependent manners, treatment with Ku-0063794 resulted in a marked decrease in the expression of p-4E-BP1 in KoTCC-1 cells compared with that with temsirolimus. Furthermore, the growth-inhibitory effect of both mTOR inhibitors was shown to be proportional to the expression levels of p-4E-BP1.
  
  
  CONCLUSIONS
  The phosphorylation status of 4E-BP1 appeared to be correlated with the prognosis of patients with muscle-invasive BC following radical cystectomy as well as the sensitivities of BC cells to mTOR inhibitors; therefore, the inactivation of 4E-BP1 using Ku-0063794 may be a promising novel approach for muscle-invasive BC.
authors.affiliation: Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Masatomo
authors.initials: M
authors.lastname: Nishikawa
authors.affiliation: Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan. Electronic address: hideakimiyake@hotmail.com.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Miyake
authors.affiliation: Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan; Department of Urology, Faculty of Medicine, Assiut University, Assiut, Egypt.
authors.forename: Hosny M
authors.initials: HM
authors.lastname: Behnsawy
authors.affiliation: Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Fujisawa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000096:biosynthesis*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D002295:Carcinoma, Transitional Cell / Q000401:mortality / Q000473:pathology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000032:analysis / Q000096:biosynthesis*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000401:mortality / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D009025:Morpholines; D010750:Phosphoproteins; D011743:Pyrimidines; C541932:Ku 0063794; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: 4E-BP1; Invasive urothelial carcinoma of bladder; Ku-0063794; mTOR pathway