Cordycepin inhibits protein synthesis and cell adhesion through effects on signal transduction.
Cordycepin inhibits protein synthesis and cell adhesion through effects on signal transduction.
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DOI：
10.1074/jbc.m109.071159
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发表时间：
2010-01-22
期刊：
影响因子：
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通讯作者：
de Moor CH
中科院分区：
文献类型：
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作者：
Wong YY;Moon A;Duffin R;Barthet-Barateig A;Meijer HA;Clemens MJ;de Moor CH
3 ′-脱氧腺苷（3 ′-Deoxyadenosine），又称虫草素（cordycepin），是一种已知的多聚腺苷酸化抑制剂，具有广泛的生物学活性，包括抗增殖、促凋亡和抗炎作用。在这项研究中，我们证实，虫草素减少聚（A）尾巴的长度，与一些mRNA比其他更敏感。低剂量的虫草素引起poly（A）变化，也降低了NIH 3T3成纤维细胞的增殖。在较高剂量的药物，我们观察到细胞附着的抑制和减少局灶性粘连。此外，我们观察到了与抑制哺乳动物雷帕霉素靶蛋白（mTOR）信号传导相关的总蛋白合成的强烈抑制，如通过Akt激酶和4E结合蛋白（4EBP）磷酸化的减少所观察到的。在4EBP敲除细胞中，虫草素对翻译的影响强烈降低，证实了这种修饰的作用。此外，AMP激活的激酶（AMPK）也被激活。AMPK的抑制阻止了虫草素的翻译抑制，并消除了4EBP 1的去磷酸化，表明虫草素对mTOR信号转导和蛋白质合成的影响是由AMPK激活介导的。我们的结论是，许多报道的虫草素的生物学效应可能是由于其对mTOR和AMPK信号的影响。
3′-Deoxyadenosine, also known as cordycepin, is a known polyadenylation inhibitor with a large spectrum of biological activities, including anti-proliferative, pro-apoptotic and anti-inflammatory effects. In this study we confirm that cordycepin reduces the length of poly(A) tails, with some mRNAs being much more sensitive than others. The low doses of cordycepin that cause poly(A) changes also reduce the proliferation of NIH3T3 fibroblasts. At higher doses of the drug we observed inhibition of cell attachment and a reduction of focal adhesions. Furthermore, we observed a strong inhibition of total protein synthesis that correlates with an inhibition of mammalian target of rapamycin (mTOR) signaling, as observed by reductions in Akt kinase and 4E-binding protein (4EBP) phosphorylation. In 4EBP knock-out cells, the effect of cordycepin on translation is strongly reduced, confirming the role of this modification. In addition, the AMP-activated kinase (AMPK) was shown to be activated. Inhibition of AMPK prevented translation repression by cordycepin and abolished 4EBP1 dephosphorylation, indicating that the effect of cordycepin on mTOR signaling and protein synthesis is mediated by AMPK activation. We conclude that many of the reported biological effects of cordycepin are likely to be due to its effects on mTOR and AMPK signaling.