Wogonin and related natural flavones are inhibitors of CDK9 that induce apoptosis in cancer cells by transcriptional suppression of Mcl-1.
Wogonin and related natural flavones are inhibitors of CDK9 that induce apoptosis in cancer cells by transcriptional suppression of Mcl-1.
复制标题
DOI：
10.1038/cddis.2011.66
复制
发表时间：
2011-07-21
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
含汉黄芩素的中药黄芩已成功用于治疗多种疾病。汉黄芩素在体内可诱导不同的癌细胞凋亡，并抑制人癌异种移植物的生长。然而，其直接目标仍然不明。在这项研究中，我们首次证明，汉黄芩素和结构上相关的天然黄酮，例如，芹菜素，白杨素和毛地黄黄酮，是细胞周期蛋白依赖性激酶9（CDK 9）的抑制剂和块磷酸化的羧基末端结构域的RNA聚合酶II在Ser 2。这种作用导致RNA合成减少，随后快速下调短寿命抗凋亡蛋白髓样细胞白血病1（Mcl-1），导致癌细胞中的凋亡诱导。我们表明，基因抑制Mcl-1或CDK 9表达的siRNA是足以模拟黄酮诱导的细胞凋亡。下拉和在计算机对接研究表明，汉黄芩素直接结合CDK 9，推测ATP结合口袋。相反，汉黄芩素在抑制CDK 9活性的剂量下不抑制CDK 2、CDK 4和CDK 6。此外，我们发现汉黄芩素优先抑制CDK 9在恶性淋巴细胞相比，正常的。因此，我们的研究揭示了天然黄酮抗癌作用的新机制，并支持CDK 9作为肿瘤学治疗靶点。
The wogonin-containing herb Scutellaria baicalensis has successfully been used for curing various diseases in traditional Chinese medicine. Wogonin has been shown to induce apoptosis in different cancer cells and to suppress growth of human cancer xenografts in vivo. However, its direct targets remain unknown. In this study, we demonstrate for the first time that wogonin and structurally related natural flavones, for example, apigenin, chrysin and luteolin, are inhibitors of cyclin-dependent kinase 9 (CDK9) and block phosphorylation of the carboxy-terminal domain of RNA polymerase II at Ser2. This effect leads to reduced RNA synthesis and subsequently rapid downregulation of the short-lived anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1) resulting in apoptosis induction in cancer cells. We show that genetic inhibition of Mcl-1 or CDK9 expression by siRNA is sufficient to mimic flavone-induced apoptosis. Pull-down and in silico docking studies demonstrate that wogonin directly binds to CDK9, presumably to the ATP-binding pocket. In contrast, wogonin does not inhibit CDK2, CDK4 and CDK6 at doses that inhibit CDK9 activity. Furthermore, we show that wogonin preferentially inhibits CDK9 in malignant compared with normal lymphocytes. Thus, our study reveals a new mechanism of anti-cancer action of natural flavones and supports CDK9 as a therapeutic target in oncology.
登录
查看更多内容
影响因子：
3.8
作者：
Schulze-Bergkamen H;Fleischer B;Schuchmann M;Weber A;Weinmann A;Krammer PH;Galle PR
通讯作者：
Galle PR
影响因子：
11.4
作者：
Baumli, Sonja;Lolli, Graziano;Johnson, Louise N.
通讯作者：
Johnson, Louise N.
影响因子：
2.7
作者：
Liu, Ai-Lin;Liu, Bo;Du, Guan-Hua
通讯作者：
Du, Guan-Hua
影响因子：
6.4
作者：
Chung, Heekyoung;Jung, Youn -Mi;Kong, Gu
通讯作者：
Kong, Gu
影响因子：
11.5
作者：
Hussain, Syed-Rehan A.;Cheney, Carolyn M.;Byrd, John C.
通讯作者：
Byrd, John C.