title: Inhibition of presenilins attenuates proliferation and invasion in bladder cancer cells through multiple pathways.
abstract: OBJECTIVE
  Presenilin (PS)/γ-secretase is a key protease that initiates various biological processes. We investigated the effect of PS/γ-secretase on the expression and inhibition of urothelial cell carcinoma of bladder (UCB) as a potential alternative therapeutic target for UCB.
  
  
  METHODS
  PS-1 and PS-2 were identified in normal and malignant human bladder transitional cells by immunohistochemistry. We blocked PSs using a PS/γ-secretase inhibitor N-(N-[3,5-difluorophenacetyl]-L-alanyl)-S-phenylglycine-t-butylester (DAPT), and the proliferative and invasive potential of UCB cells SW780, BIU-87, 5637, and T24, and human normal urothelial cell line SV-HUC-1 were analyzed using Western blot, cell viability test, flow cytometry, and transwell assay. All experiments were repeated at least 3 times.
  
  
  RESULTS
  Human bladder samples of UCB, SW780, BIU-87, 5637, and T24 cells expressed higher PS-1 compared with normal ones. Cell vitality test demonstrated that DAPT attenuated UCB cell proliferation more than SV-HUC-1. Flow cytometry and transwell assay showed that T24 cells were arrested at G1/S checkpoint and its invasive ability was impaired. Western blot assay markedly showed that protein levels of CD44-intracellular domain, insulinlike growth factor-1Rβ, extracellular regulated protein kinase 1/2, cyclin D1, proliferating cell nuclear antigen, and matrix metalloproteinase-9 were downregulated by DAPT, whereas vascular endothelial growth factor receptor-2 and vascular endothelial growth factor-165 were upregulated.
  
  
  CONCLUSIONS
  Our study revealed that PS-1 might be implicated in the proliferation and invasion of UCB, and that it may serve as a potential therapeutic target for UCB, but further studies are warranted to verify the effects of inhibition of PS/γ-secretase on angiogenesis.
authors.affiliation: Department of Urology, Peking University First Hospital; Institute of Urology, Peking University, Beijing, China.
authors.forename: Jun-Wei
authors.initials: JW
authors.lastname: Gai
authors.affiliation: Department of Urology, China PLA General Hospital, Beijing, China.
authors.forename: Wasilijiang
authors.initials: W
authors.lastname: Wahafu
authors.affiliation: Department of Anesthesiology and Intensive Care, Peking University First Hospital, Beijing, China.
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Hsieh
authors.affiliation: HeDong Center for Disease Control and Prevention, Tianjin, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Orthopaedic Surgery, Beijing Jishuitan Hospital, Fourth Clinical College of Peking University, Beijing, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Urology, Tsinghua University First Hospital, Beijing, China.
authors.forename: Sheng-Wen
authors.initials: SW
authors.lastname: Li
authors.affiliation: Department of Urology, Peking University First Hospital; Institute of Urology, Peking University, Beijing, China.
authors.forename: Bei
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Urology, Peking University First Hospital; Institute of Urology, Peking University, Beijing, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: He
authors.affiliation: Department of Urology, Tsinghua University First Hospital, Beijing, China. Electronic address: ghduro@yahoo.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Urology, Peking University First Hospital; Institute of Urology, Peking University, Beijing, China. Electronic address: Jinjie@vip.163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Jin
mesh_terms: D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015653:Cystectomy; D005260:Female; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D053763:Presenilins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery
chemical_list: D053763:Presenilins; D053829:Amyloid Precursor Protein Secretases
keywords: Bladder cancer; DAPT; Presenilin; Urothelial cell carcinoma of the urinary bladder; γ-Secretase