PMID- 25618298 OWN - NLM STAT- MEDLINE DCOM- 20160226 LR - 20211203 IS - 1873-2496 (Electronic) IS - 1078-1439 (Linking) VI - 33 IP - 4 DP - 2015 Apr TI - Significance of 4E-binding protein 1 as a therapeutic target for invasive urothelial carcinoma of the bladder. PG - 166.e9-15 LID - S1078-1439(14)00459-1 [pii] LID - 10.1016/j.urolonc.2014.12.006 [doi] AB - 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. CI - Copyright (c) 2015 Elsevier Inc. All rights reserved. FAU - Nishikawa, Masatomo AU - Nishikawa M AD - Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan. FAU - Miyake, Hideaki AU - Miyake H AD - Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan. Electronic address: hideakimiyake@hotmail.com. FAU - Behnsawy, Hosny M AU - Behnsawy HM AD - Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan; Department of Urology, Faculty of Medicine, Assiut University, Assiut, Egypt. FAU - Fujisawa, Masato AU - Fujisawa M AD - Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan. LA - eng PT - Journal Article DEP - 20150121 PL - United States TA - Urol Oncol JT - Urologic oncology JID - 9805460 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers, Tumor) RN - 0 (Cell Cycle Proteins) RN - 0 (EIF4EBP1 protein, human) RN - 0 (Morpholines) RN - 0 (Phosphoproteins) RN - 0 (Pyrimidines) RN - 81HJG228AB (Ku 0063794) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Adaptor Proteins, Signal Transducing/analysis/*biosynthesis MH - Adult MH - Aged MH - Aged, 80 and over MH - Antineoplastic Agents/pharmacology MH - Biomarkers, Tumor/*analysis MH - Blotting, Western MH - Carcinoma, Transitional Cell/mortality/*pathology MH - Cell Cycle Proteins MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Disease-Free Survival MH - Female MH - Humans MH - Immunohistochemistry MH - Kaplan-Meier Estimate MH - Male MH - Middle Aged MH - Morpholines/pharmacology MH - Neoplasm Invasiveness MH - Phosphoproteins/analysis/*biosynthesis MH - Pyrimidines/pharmacology MH - Signal Transduction/drug effects/physiology MH - TOR Serine-Threonine Kinases/metabolism MH - Urinary Bladder Neoplasms/mortality/*pathology OTO - NOTNLM OT - 4E-BP1 OT - Invasive urothelial carcinoma of bladder OT - Ku-0063794 OT - mTOR pathway EDAT- 2015/01/27 06:00 MHDA- 2016/02/27 06:00 CRDT- 2015/01/26 06:00 PHST- 2014/09/18 00:00 [received] PHST- 2014/12/12 00:00 [revised] PHST- 2014/12/12 00:00 [accepted] PHST- 2015/01/26 06:00 [entrez] PHST- 2015/01/27 06:00 [pubmed] PHST- 2016/02/27 06:00 [medline] AID - S1078-1439(14)00459-1 [pii] AID - 10.1016/j.urolonc.2014.12.006 [doi] PST - ppublish SO - Urol Oncol. 2015 Apr;33(4):166.e9-15. doi: 10.1016/j.urolonc.2014.12.006. Epub 2015 Jan 21.