title: Simvastatin induces cell cycle arrest and inhibits proliferation of bladder cancer cells via PPARγ signalling pathway.
abstract: 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 PPARγ-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/GSK3β. 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 PPARγ-antagonist (GW9662), whereas the treatment of PPARα-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 PPARγ signalling pathway.
authors: Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
authors: Gang
authors: G
authors: Wang
authors: Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
authors: Rui
authors: R
authors: Cao
authors: Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
authors: Yongzhi
authors: Y
authors: Wang
authors: Department of Endocrinology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China.
authors: Guofeng
authors: G
authors: Qian
authors: Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD, USA.
authors: Han C
authors: HC
authors: Dan
authors: Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.|College of Life Science, Wuhan University, Wuhan, China.
authors: Wei
authors: W
authors: Jiang
authors: College of Life Science, Wuhan University, Wuhan, China.
authors: Lingao
authors: L
authors: Ju
authors: College of Life Science, Wuhan University, Wuhan, China.
authors: Min
authors: M
authors: Wu
authors: Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.|Center for Medical Science Research, Zhongnan Hospital of Wuhan University, Wuhan, China.
authors: Yu
authors: Y
authors: Xiao
authors: Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
authors: Xinghuan
authors: X
authors: Wang
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000096:biosynthesis; D051358:Cyclin-Dependent Kinase 4 / Q000096:biosynthesis; D051361:Cyclin-Dependent Kinase 6 / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology; D010080:Oxazoles / Q000494:pharmacology; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology; D001743:Urinary Bladder / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000970:Antineoplastic Agents; C530104:CCND1 protein, human; C449302:GW 6471; D010080:Oxazoles; D047495:PPAR gamma; D019938:Cyclin D1; D014443:Tyrosine; D019821:Simvastatin; C512478:EGFR protein, human; D066246:ErbB Receptors; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6