The p70S6K Specific Inhibitor PF-4708671 Impedes Non-Small Cell Lung Cancer Growth.
The p70S6K Specific Inhibitor PF-4708671 Impedes Non-Small Cell Lung Cancer Growth.
复制标题
p70S6K 特异性抑制剂 PF-4708671 阻碍非小细胞肺癌生长
DOI：
10.1371/journal.pone.0147185
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Li WM
中科院分区：
文献类型：
--
作者：
Qiu ZX;Sun RF;Mo XM;Li WM
背景 p70S6K 作为一种丝氨酸/苏氨酸蛋白激酶，在肿瘤细胞中发挥着重要作用。有证据表明，p70S6K 和磷酸化 p70S6K (p-p70S6K) 在各种肿瘤组织中过度表达，这些蛋白被确定为非小细胞肺癌 (NSCLC) 的独立预后标志物。在本研究中，我们探讨了 p70S6K 特异性抑制剂 PF-4708671 在 NSCLC 中的作用。方法 用 0.1μM、0.3μM、1μM、3μM 和 10μM 5 个不同浓度的 PF-4708671 处理 3 个 NSCLC 细胞系（A549、SK-MES-1 和 NCI-H460），并通过 Western-blot 测定蛋白水平。然后，在体外（细胞增殖、凋亡、细胞周期分布和侵袭）和体内评估 PF-4708671 的作用。结果 PF-4708671 显着降低 p-p70S6K 和下游效应子 S6 的表达水平。恰恰相反，用 PF-4708671 处理后，BAD、Caspase3 和 ERK 的下游蛋白水平有所增加。此外，PF-4708671在体外显着抑制A549、SK-MES-1和NCI-H460细胞的细胞增殖和侵袭能力，导致细胞周期停滞在G0-G1期。在所评估的三种 NSCLC 细胞系中观察到 PF-4708671 对细胞凋亡的影响有限。重要的是，PF-4708671可以抑制裸鼠体内肿瘤的发生。结论 这些结果表明p70S6K特异性抑制剂PF-4708671在体外和体内对NSCLC肿瘤发生具有抑制作用。因此，P70S6K应被视为新的潜在治疗靶点，PF-470867可作为癌症治疗的靶向药物。
Background As a serine/threonine protein kinase, p70S6K plays an important role in tumor cells. Evidence has revealed overexpression of p70S6K and phosphorylated p70S6K (p-p70S6K) in various tumor tissues, with these proteins identified as independent prognostic markers in non-small cell lung cancer (NSCLC). In this study, we explored the role of the p70S6K specific inhibitor PF-4708671 in NSCLC. Methods Three NSCLC cell lines (A549, SK-MES-1, and NCI-H460) were treated with PF-4708671 at five different concentrations, including 0.1μM, 0.3μM, 1μM, 3μM and 10μM, and protein levels were determined by Western-blot. Then, PF-4708671’s effects were assessed both in vitro (cell proliferation, apoptosis, cell cycle distribution, and invasion) and in vivo. Results The expression levels of p-p70S6K and the downstream effector S6 were significantly reduced by PF-4708671. Diametrically opposite, the downstream protein levels of BAD, Caspase3 and ERK had increased after treatment with PF-4708671. In addition, PF-4708671 drastically inhibited cell proliferation and invasion ability in A549, SK-MES-1 and NCI-H460 cells in vitro, causing cell cycle arrest in G0-G1 phase. Limited effects of PF-4708671 were observed on apoptosis in the three NSCLC cell lines assessed. Importantly, PF-4708671 could inhibit tumorigenesis in nude mice in vivo. Conclusion These findings demonstrated that the p70S6K specific inhibitor PF-4708671 has inhibitory effects on NSCLC tumorigenesis in vitro and in vivo. Therefore, P70S6K should be considered a new potential therapeutic target, and PF-470867 may be used as targeted drug for cancer treatment.