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.

MATERIALS AND 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: Jun-Wei Gai, Wasilijiang Wahafu, Ya-Ching Hsieh, Miao Liu, Liang Zhang, Sheng-Wen Li, Bei Zhang, Qun He, Hui Guo, Jie Jin
• Journal: Urologic oncology (Urol Oncol) Vol. 32 Issue 1 Pg. 36.e19-25 (Jan 2014) ISSN: 1873-2496 [Electronic] United States
• PMID: 23628311 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Presenilins
• Amyloid Precursor Protein Secretases

Topics

• Aged
• Amyloid Precursor Protein Secretases (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• Cystectomy
• Female
• Flow Cytometry
• G1 Phase (drug effects)
• Humans
• Immunohistochemistry
• Male
• Middle Aged
• Neoplasm Invasiveness
• Neovascularization, Pathologic
• Presenilins (antagonists & inhibitors, metabolism)
• S Phase (drug effects)
• Urinary Bladder Neoplasms (drug therapy, metabolism, pathology, surgery)