Baicalein upregulates DDIT4 expression which mediates mTOR inhibition and growth inhibition in cancer cells.
Baicalein upregulates DDIT4 expression which mediates mTOR inhibition and growth inhibition in cancer cells.
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DOI：
10.1016/j.canlet.2014.12.033
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发表时间：
2015-03-28
期刊：
影响因子：
9.7
通讯作者：
Yim JH
中科院分区：
文献类型：
--
作者：
Wang Y;Han E;Xing Q;Yan J;Arrington A;Wang C;Tully D;Kowolik CM;Lu DM;Frankel PH;Zhai J;Wen W;Horne D;Yip MLR;Yim JH
黄芩素是一种天然黄酮，具有抗癌特性。利用基因芯片我们发现DDIT 4是黄芩素在癌细胞中诱导的最高转录物。我们通过定量RT-PCR和免疫印迹证实了在多种癌细胞系中DDIT 4的大的、剂量相关的表达，其与生长抑制相关。时程实验表明，DDIT 4是快速诱导型的，在体外维持高表达数天。基于对p53敲除细胞的评价，DDIT 4表达的诱导是p53非依赖性的。由于已知DDIT 4抑制mTORC 1活性，我们证实黄芩素抑制mTORC 1靶点的磷酸化。使用RNA干扰，我们证明，mTORC 1的活性和生长抑制黄芩素减弱敲低DDIT 4。我们还证明了黄芩素在乳腺癌小鼠模型中对已建立的肿瘤的抑制作用，肿瘤中DDIT 4表达增加。最后，我们证明了黄芩素上调DDIT 4，并导致mTORC 1和铂耐药癌细胞的生长抑制，与铂化疗治疗形成鲜明对比。这些研究表明黄芩素通过DDIT 4表达抑制mTORC 1，并且可能在癌症化疗和化学预防中有用。
Baicalein is a natural flavone that exhibits anticancer properties. Using microarrays we found that DDIT4 was the highest transcript induced by baicalein in cancer cells. We confirmed in multiple cancer cell lines large, dose-related expression of DDIT4 by quantitative RT-PCR and immunoblot, which correlates with growth inhibition. Time course experiments demonstrate that DDIT4 is rapidly inducible, with high expression maintained for several days in vitro. Induction of DDIT4 expression is p53 independent based on evaluation of p53 knockout cells. Since DDIT4 is known to inhibit mTORC1 activity we confirmed that baicalein suppresses phosphorylation of mTORC1 targets. Using RNA interference we demonstrate that mTORC1 activity and growth inhibition by baicalein is attenuated by knockdown of DDIT4. We furthermore demonstrate suppression of established tumors by baicalein in a mouse model of breast cancer with increased DDIT4 expression in the tumors. Finally, we demonstrate that baicalein upregulates DDIT4 and causes mTORC1 and growth inhibition in platinum resistant cancer cells in marked contrast to platinum chemotherapy treatment. These studies demonstrate that baicalein inhibits mTORC1 through DDIT4 expression, and may be useful in cancer chemotherapy and chemoprevention.
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影响因子：
3.7
作者：
Chen K;Zhang S;Ji Y;Li J;An P;Ren H;Liang R;Yang J;Li Z
通讯作者：
Li Z
影响因子：
5.7
作者：
Gao J;Wang Y;Xing Q;Yan J;Senthil M;Akmal Y;Kowolik CM;Kang J;Lu DM;Zhao M;Lin Z;Cheng CH;Yip ML;Yim JH
通讯作者：
Yim JH
影响因子：
8
作者：
Pamment, J;Ramsay, E;Ball, KL
通讯作者：
Ball, KL
DOI：
10.1016/j.bbrc.2008.12.079
发表时间：
2009-02-06
影响因子：
3.1
作者：
Whitney, Michael L.;Jefferson, Leonard S.;Kimball, Scot R.
通讯作者：
Kimball, Scot R.
影响因子：
5
作者：
Hsu, SL;Hsieh, YC;Chou, CJ
通讯作者：
Chou, CJ