Simvastatin induces cell cycle arrest and inhibits proliferation of bladder cancer cells via PPARγ signalling pathway

被引:110
作者
Wang, Gang [1 ]
Cao, Rui [1 ]
Wang, Yongzhi [1 ]
Qian, Guofeng [2 ]
Dan, Han C. [3 ]
Jiang, Wei [4 ,5 ]
Ju, Lingao [5 ]
Wu, Min [5 ]
Xiao, Yu [1 ,6 ]
Wang, Xinghuan [1 ]
机构
[1] Wuhan Univ, Zhongnan Hosp, Dept Urol, Wuhan, Peoples R China
[2] Zhejiang Univ, Affiliated Hosp 1, Dept Endocrinol, Hangzhou, Zhejiang, Peoples R China
[3] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA
[4] Wuhan Univ, Sch Med, Med Res Inst, Wuhan, Peoples R China
[5] Wuhan Univ, Coll Life Sci, Wuhan, Peoples R China
[6] Wuhan Univ, Zhongnan Hosp, Ctr Med Sci Res, Wuhan, Peoples R China
关键词
ACTIVATED RECEPTOR-GAMMA; RADICAL CYSTECTOMY; DEPENDENT PATHWAY; LIPID RAFT; ALPHA; RISK; DEATH; PREVENTION; EXPRESSION; THERAPY;
D O I
10.1038/srep35783
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Simvastatin is currently one of the most common drugs for old patients with hyperlipidemia, hypercholesterolemia and atherosclerotic diseases by reducing cholesterol level and anti-lipid properties. Importantly, simvastatin has also been reported to have anti-tumor effect, but the underlying mechanism is largely unknown. We collected several human bladder samples and performed microarray. Data analysis suggested bladder cancer (BCa) was significantly associated with fatty acid/lipid metabolism via PPAR signalling pathway. We observed simvastatin did not trigger BCa cell apoptosis, but reduced cell proliferation in a dose- and time-dependent manner, accompanied by PPAR gamma-activation. Moreover, flow cytometry analysis indicated that simvastatin induced cell cycle arrest at G0/G1 phase, suggested by downregulation of CDK4/6 and Cyclin D1. Furthermore, simvastatin suppressed BCa cell metastasis by inhibiting EMT and affecting AKT/GSK3 beta. More importantly, we found that the cell cycle arrest at G0/G1 phase and the alterations of CDK4/6 and Cyclin D1 triggered by simvastatin could be recovered by PPAR gamma-antagonist (GW9662), whereas the treatment of PPAR alpha-antagonist (GW6471) shown no significant effects on the BCa cells. Taken together, our study for the first time revealed that simvastatin inhibited bladder cancer cell proliferation and induced cell cycle arrest at G1/G0 phase via PPAR gamma signalling pathway.
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页数:13
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