Rictor-dependent AKT activation and inhibition of urothelial carcinoma by rapamycin

doi:10.1016/j.urolonc.2009.11.009

中山醫學大學機構典藏 CSMUIR > 醫學院 > 醫學系 > 期刊論文 > Item 310902500/4363

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Title:	Rictor-dependent AKT activation and inhibition of urothelial carcinoma by rapamycin
Authors:	Wu, Ming-Ju Chang, Chi-Hao Chiu, Yung-Tsung Wen, Mei-Chin Shu, Kuo-Hsiung Li, Jian-Ri Chiu, Kun-Yuan Chen, Yen-Ta
Contributors:	中山醫學大學醫學系
Keywords:	AKT Rapamycin Rictor Urothelial carcinoma VEGF
Date:	2009-11-10
Issue Date:	2012-07-24T06:42:52Z (UTC)
ISSN:	1078-1439
Abstract:	Objective We previously reported a very high cumulative incidence of urothelial carcinoma in Taiwanese kidney transplant recipients. Rapamycin, the inhibitor of mTOR Complex 1, provides alternative immunosuppressive therapy after kidney transplantation with less neoplastic potential. We examined the in vivo and in vitro effects of rapamycin on urothelial carcinoma. Materials and methods The rat model of urothelial carcinoma was induced by 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in Fischer F344 rats. The anti-tumor effect of rapamycin was assessed grossly, microscopically, and by Western blot analysis. The mechanism of rapamycin's attenuation of urothelial carcinoma was also evaluated by T24 cells. Results Rapamycin significantly reduced urinary bladder tumor growth in the rat model of 0.05% BBN-induced urothelial carcinoma (P < 0.001). The blood trough levels of rapamycin were correlated with the occurrence of urothelial carcinoma. In vitro, rapamycin also inhibited the cell proliferation, migration, and invasion, as well as the protein expression of vascular endothelial growth factor-A of T24 urothelial carcinoma cells, whereas rapamycin did not induce significant apoptosis in T24 cells. Rapamycin decreased the expression of phospho-mTOR, phospho-S6K, cyclin D1, and VEGF-A. Rapamycin also activated AKT in T24 cells in the rat model of urothelial carcinoma. The rapamycin-associated activation of AKT was inhibited by rictor siRNA, but not raptor siRNA. Conclusions This study provides in vitro and in vivo evidence that rapamycin may inhibit the development of urothelial carcinoma. The present findings also suggest rictor-dependent AKT activation as a consequence of mTORC1 inhibition.
URI:	https://ir.csmu.edu.tw:8080/ir/handle/310902500/4363 http://dx.doi.org/10.1016/j.urolonc.2009.11.009
Relation:	Urologic Oncology: Seminars and Original Investigations Volume 30, Issue 1, January–February 2012, Pages 69–77
Appears in Collections:	[醫學系] 期刊論文

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