Anticancer Efficacy of Simvastatin on Prostate Cancer Cells and Tumor Xenografts Is Associated with Inhibition of Akt and Reduced Prostate-Specific Antigen Expression
Anticancer Efficacy of Simvastatin on Prostate Cancer Cells and Tumor Xenografts Is Associated with Inhibition of Akt and Reduced Prostate-Specific Antigen Expression
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DOI：
10.1124/jpet.110.174870
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发表时间：
2011-02-01
影响因子：
3.5
通讯作者：
Somanath, Payaningal R.
中科院分区：
文献类型：
--
作者：
Kochuparambil, Samith T.;Al-Husein, Belal;Somanath, Payaningal R.
前列腺癌是美国男性癌症相关死亡的第二大原因。人们对他汀类药物治疗癌症的潜在益处重新产生了兴趣。辛伐他汀是一种广泛使用的预防心血管事件的仿制药，因其对细胞增殖和炎症的影响而闻名，这两个关键过程也决定了肿瘤的生长速度。尽管越来越多的证据表明他汀类药物有可能降低许多癌症的风险，但他汀类药物的促癌作用和抗癌作用存在差异。在本研究中，我们试图探讨辛伐他汀对前列腺癌细胞中Akt通路的影响，以及在体外对各种细胞功能和体内肿瘤生长的调节。辛伐他汀对LNCaP（雄激素依赖性）和PC3（雄激素非依赖性）细胞的时间和剂量依赖性效应表明，浓度低至25 μ M的辛伐他汀足以抑制血清刺激的Akt活性。与此类似，辛伐他汀治疗可显著抑制血清诱导的细胞迁移、侵袭、集落形成和增殖。在PC3细胞系中，腺病毒介导的组成活性Akt （myristoylated Akt）的表达挽救了辛伐他汀介导的对集落形成的影响。裸鼠PC3异种移植模型显示，辛伐他汀治疗后肿瘤生长减少，Akt活性降低，前列腺特异性抗原（PSA）水平降低。我们的研究结果证明了辛伐他汀对前列腺癌的治疗益处，并提示辛伐他汀、Akt活性调节和前列腺肿瘤中PSA表达之间存在联系。
Prostate cancer is the second-leading cause of cancer-associated death among men in the United States. There has been renewed interest in the potential therapeutic benefits of statins for cancer. Simvastatin, a widely used generic drug for preventing cardiovascular events, is well known for its effects on cellular proliferation and inflammation, two key processes that also determine the rate of tumor growth. Although a growing body of evidence suggests that statins have the potential to reduce the risk of many cancers, there are discrepancies over the pro-and anticancer effects of statins. In the current study, we sought to investigate the effects of simvastatin on the Akt pathway in prostate cancer cells with respect to the regulation of various cell functions in vitro and tumor growth in vivo. Time- and dose-dependent effects of simvastatin on LNCaP (androgen-dependent) and PC3 (androgen-independent) cells indicate that treatment with simvastatin at concentrations as low as 25 mu M was sufficient to inhibit serum-stimulated Akt activity. Akin to this, treatment with simvastatin significantly inhibited serum-induced cell migration, invasion, colony formation, and proliferation. Simvastatin-mediated effects on colony formation were rescued by adenovirus-mediated expression of constitutively active Akt (myristoylated Akt) in PC3 cell lines. A PC3 xenograft model performed in nude mice exhibited reduced tumor growth with simvastatin treatment associated with decreased Akt activity and reduced prostate-specific antigen (PSA) levels. Our findings demonstrate the therapeutic benefits of simvastatin for prostate cancer and suggest a link between simvastatin, regulation of Akt activity, and PSA expression in prostate tumors.