P70S6K and Elf4E Dual Inhibition Is Essential to Control Bladder Tumor Growth and Progression in Orthotopic Mouse Non-muscle Invasive Bladder Tumor Model.
10.3346/jkms.2015.30.3.308
- Author:
Byung Hoon CHI
1
;
Soon Ja KIM
;
Ho Kyung SEO
;
Hye Hyun SEO
;
Sang Jin LEE
;
Jong Kyou KWON
;
Tae Jin LEE
;
In Ho CHANG
Author Information
1. Department of Urology, Chung-Ang University College of Medicine, Seoul, Korea. caucih@cau.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
Urinary Bladder Neoplasms;
Mouse Orthotopic Model;
mTOR
- MeSH:
Animals;
Cell Line;
Cell Proliferation/drug effects/genetics;
Cell Survival/drug effects;
Disease Progression;
Eukaryotic Initiation Factor-4E/*antagonists & inhibitors/genetics;
Female;
Mice;
Mice, Nude;
Mucous Membrane/pathology;
Phosphorylation/drug effects;
RNA Interference;
RNA, Small Interfering;
Ribosomal Protein S6 Kinases, 70-kDa/*antagonists & inhibitors/genetics;
Signal Transduction/drug effects;
Sirolimus/*pharmacology;
TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism;
Urinary Bladder Neoplasms/genetics/*pathology;
Urothelium/pathology
- From:Journal of Korean Medical Science
2015;30(3):308-316
- CountryRepublic of Korea
- Language:English
-
Abstract:
We investigated how the dual inhibition of the molecular mechanism of the mammalian target of the rapamycin (mTOR) downstreams, P70S6 kinase (P70S6K) and eukaryotic initiation factor 4E (eIF4E), can lead to a suppression of the proliferation and progression of urothelial carcinoma (UC) in an orthotopic mouse non-muscle invasive bladder tumor (NMIBT) model. A KU-7-luc cell intravesically instilled orthotopic mouse NMIBC model was monitored using bioluminescence imaging (BLI) in vivo by interfering with different molecular components using rapamycin and siRNA technology. We then analyzed the effects on molecular activation status, cell growth, proliferation, and progression. A high concentration of rapamycin (10 microM) blocked both P70S6K and elF4E phosphorylation and inhibited cell proliferation in the KU-7-luc cells. It also reduced cell viability and proliferation more than the transfection of siRNA against p70S6K or elF4E. The groups with dual p70S6K and elF4E siRNA, and rapamycin reduced tumor volume and lamina propria invasion more than the groups with p70S6K or elF4E siRNA instillation, although all groups reduced photon density compared to the control. These findings suggest that both the mTOR pathway downstream of eIF4E and p70S6K can be successfully inhibited by high dose rapamycin only, and p70S6K and Elf4E dual inhibition is essential to control bladder tumor growth and progression.
