Simvastatin Inhibits Renal Cancer Cell Growth and Metastasis via AKT/mTOR, ERK and JAK2/STAT3 Pathway

• DOI: 10.1371/journal.pone.0062823
• Publication Date: 2013-05-17T17:13:43Z
• Authors: Zhiqing Fang; Yueqing Tang; Juanjuan Fang; Zunlin Zhou; Zhaoquan Xing; Zhaoxin Guo; Xiaoyu Guo; Weichang Wang; Wei Jiao; Zhonghua Xu; Zhaoxu Liu
• Keywords: STAT3 Transcription Factor; Simvastatin; MAP Kinase Signaling System; Science; Blotting, Western; Mice, Nude; Apoptosis; Mice; 03 medical and health sciences; 0302 clinical medicine; Cell Movement; Cell Line, Tumor; In Situ Nick-End Labeling; Animals; Humans; Neoplasm Metastasis; Phosphorylation; Carcinoma, Renal Cell; Cell Proliferation; TOR Serine-Threonine Kinases; Q; R; Janus Kinase 2; 3. Good health; Medicine; RNA Interference; Research Article

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.