title: Simvastatin inhibits renal cancer cell growth and metastasis via AKT/mTOR, ERK and JAK2/STAT3 pathway.
abstract: Renal cell carcinoma (RCC) is the most lethal type of genitourinary cancer due to its occult onset and resistance to chemotherapy and radiation. Recently, accumulating evidence has suggested stains, inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, were associated with the risk reduction of cancer. In the present study, we aimed to investigate the potential effects of simvastatin on RCC cells and the underlying mechanisms by which simvastatin exerted its actions. With cell viability, colony formation, and flow cytometric apoptosis assays, we found that simvastatin potently suppressed cell growth of A498 and 786-O cells in a time- and dose- dependent manner. Consistently, the xenograft model performed in nude mice exhibited reduced tumor growth with simvastatin treatment. In addition, the inhibitory effects of simvastatin on migration and invasion were also observed in vitro. Mechanically, we presented that simvastatin could suppress the proliferation and motility of RCC cells via inhibiting the phosphorylation of AKT, mTOR, and ERK in a time- and dose- dependent manner. Further investigation of the underlying mechanism revealed simvastatin could exert the anti-tumor effects by suppressing IL-6-induced phosphorylation of JAK2 and STAT3. In conclusion, these findings suggested that simvastatin-induced apoptosis and its anti-metastasis activity in RCC cells were accompanied by inhibition of AKT/mTOR, ERK, and JAK2/STAT3 pathways, which imply that simvastatin may be a potential therapeutic agent for the treatment of RCC patients.
authors.affiliation: Department of Urology, Qilu Hospital of Shandong University, Ji'nan, Shandong, China.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Fang
authors.forename: Yueqing
authors.initials: Y
authors.lastname: Tang
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Fang
authors.forename: Zunlin
authors.initials: Z
authors.lastname: Zhou
authors.forename: Zhaoquan
authors.initials: Z
authors.lastname: Xing
authors.forename: Zhaoxin
authors.initials: Z
authors.lastname: Guo
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Guo
authors.forename: Weichang
authors.initials: W
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Jiao
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Xu
authors.forename: Zhaoxu
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000503:physiopathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D020287:In Situ Nick-End Labeling; D053614:Janus Kinase 2 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D050796:STAT3 Transcription Factor; D019821:Simvastatin; C546843:mTOR protein, mouse; D053614:Janus Kinase 2; D058570:TOR Serine-Threonine Kinases