Simvastatin inhibits renal cancer cell growth and metastasis via AKT/mTOR, ERK and JAK2/STAT3 pathway.
Simvastatin inhibits renal cancer cell growth and metastasis via AKT/mTOR, ERK and JAK2/STAT3 pathway.
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DOI：
10.1371/journal.pone.0062823
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Liu Z
中科院分区：
文献类型：
--
作者：
Fang Z;Tang Y;Fang J;Zhou Z;Xing Z;Guo Z;Guo X;Wang W;Jiao W;Xu Z;Liu Z
肾细胞癌（RCC）是泌尿生殖系统最致命的癌症，因为其发病隐匿，对化疗和放疗具有抵抗力。最近，越来越多的证据表明，3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂与癌症风险降低有关。本研究旨在探讨辛伐他汀对肾细胞癌细胞的作用及其机制。通过细胞活力、集落形成和流式细胞术凋亡分析，我们发现辛伐他汀以时间和剂量依赖性方式有效地抑制A498和786-O细胞的细胞生长。一致地，在裸鼠中进行的异种移植物模型显示辛伐他汀治疗的肿瘤生长减少。此外，还观察了辛伐他汀对体外迁移和侵袭的抑制作用。机制上，辛伐他汀可通过抑制AKT、mTOR和ERK的磷酸化而抑制肾癌细胞的增殖和运动，并呈时间和剂量依赖性。进一步的机制研究表明辛伐他汀可能通过抑制IL-6诱导的JAK 2和STAT 3的磷酸化而发挥抗肿瘤作用。这些结果表明，辛伐他汀诱导肾癌细胞凋亡及其抗转移活性伴随着AKT/mTOR、ERK和JAK 2/STAT 3通路的抑制，这意味着辛伐他汀可能是一种潜在的治疗肾癌患者的治疗剂。
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.
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