Farnesyl and geranylgeranyl transferase inhibitors induce G1 arrest by targeting the proteasome
Farnesyl and geranylgeranyl transferase inhibitors induce G1 arrest by targeting the proteasome
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DOI：
10.1158/0008-5472.can-05-3416
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发表时间：
2006-01-15
期刊：
影响因子：
11.2
通讯作者：
Keyomarsi, K
中科院分区：
文献类型：
--
作者：
Efuet, ET;Keyomarsi, K
类异戊二烯抑制剂作为治疗癌症的药剂正在被评估。它们的抗肿瘤活性归因于抑制Ras的翻译后修饰，这对于Ras的易位和附着到质膜以及最终参与信号转导至关重要。然而，Ras的阻断是否是观察到的抗肿瘤活性的唯一原因尚未解决。在本报告中，我们提出了一种替代机制。使用乳腺肿瘤模型，我们表明，具有内酯部分，包括他汀类药物（如洛伐他汀）和类异戊二烯抑制剂（如FTI-277和GGTI-298），介导其细胞周期抑制活性，通过阻断糜蛋白酶活性的蛋白酶体在体外。这导致细胞周期蛋白依赖性激酶抑制剂p21和p27的积累，随后发生G（1）阻滞。缺乏p21的细胞对洛伐他汀、FTI-277和GGTI-298的生长抑制活性是难治的。然而，在这些p21缺失细胞中，法尼基转移酶（如Ras）和香叶基香叶基转移酶（如RAP-1）的关键底物的异戊二烯化分别被FTI-277和GGTI-298抑制，这表明尽管这两种类异戊二烯抑制剂都达到并抑制了它们的预期靶点，但Ras和RAP-1A的异戊二烯化的抑制不足以介导G1停滞。我们还表明，细胞周期的影响可以归因于上述代理商的功能内酯部分。总的来说，我们的数据表明，FTI和GGTI以及其他含有活性内酯部分的药物通过抑制蛋白酶体和上调p21来介导G停滞，而与抑制Ras或RAP-1的异戊二烯化无关。
Isoprenoid inhibitors are being evaluated as agents for the treatment of cancer. Their antitumor activity is attributed to inhibition of post-translational modification of Ras, which is crucial for its translocation and attachment to the plasma membrane, and ultimate involvement in signal transduction. However, whether blocking of Ras is solely responsible for the observed antitumor activity is unresolved. In this report, we propose an alternate mechanism. Using breast tumor models, we show that agents possessing a lactone moiety, including statins (such as lovastatin) and the isoprenoid inhibitors (such as FTI-277 and GGTI-298), mediate their cell cycle inhibitory activities by blocking the chymotrypsin activity of the proteasome in vitro. This results in the accumulation of cyclin-dependent kinase inhibitors p21 and p27 with subse quent G(1) arrest. Cells devoid of p21 were refractory to the growth-inhibitory activity of lovastatin, FTI-277, and GGTI-298. However, in these p21 null cells, isoprenylation of key substrates of farnesyl transferase (such as Ras) and of geranylgeranyl transferase (such as RAP-1) were inhibited by FTI-277 and GGTI-298, respectively, suggesting that although both these isoprenoid inhibitors reached and inhibited their intended targets, inhibition of the isoprenylation of Ras and RAP-1A are not sufficient to mediate G, arrest. We also show that the cell cycle effects can be attributed to the functional lactone moiety of the aforementioned agents. Collectively, our data suggest that FTI and GGTI and other agents containing an active lactone moiety mediate G, arrest via inhibition of the proteasome and up-regulation of p21, independent of the inhibition of isoprenylation of Ras or RAP-1.