Isorhapontigenin (ISO) inhibited cell transformation by inducing G0/G1 phase arrest via increasing MKP-1 mRNA Stability.
Isorhapontigenin (ISO) inhibited cell transformation by inducing G0/G1 phase arrest via increasing MKP-1 mRNA Stability.
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DOI：
10.18632/oncotarget.1872
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发表时间：
2014-05-15
期刊：
影响因子：
--
通讯作者：
Huang C
中科院分区：
文献类型：
--
作者：
Gao G;Chen L;Li J;Zhang D;Fang Y;Huang H;Chen X;Huang C
中草药新分离物异漏芦皂甙元（ISO）的抗癌化学预防作用及其机制尚未被研究。在此，我们证明了在软琼脂试验中，用不同浓度的ISO处理3周可以显著抑制TPA/EGF诱导的Cl 41细胞的细胞转化，而将细胞与相同浓度的ISO共孵育可以引起G 0/G1细胞周期停滞，而对非转化细胞没有多余的细胞毒性作用。进一步的研究表明，ISO处理导致细胞周期蛋白D1下调的剂量和时间依赖性的方式。我们的研究结果表明ISO通过靶向JNK/C-Jun/AP-1的激活在转录水平调控cyclin D1。此外，我们发现ISO抑制的JNK/C-Jun/AP-1激活是通过增加MKP-1的mRNA稳定性和失活MKK 7来上调MKP-1的表达来介导的。最重要的是，MKP-1敲低可以减弱ISO介导的JNK/C-Jun激活和cyclin D1表达的抑制，以及G 0/G1细胞周期阻滞和细胞转化抑制，而FLAG-cyclin D1 T286 A突变体的异位表达也逆转了ISO诱导的G 0/G1细胞周期阻滞和细胞转化抑制。我们的研究结果表明，ISO是一个有前途的化学预防剂，通过上调mkp-1 mRNA的稳定性，这是不同的，其癌症治疗作用，下调XIAP和细胞周期蛋白D1的表达。
The cancer chemopreventive property of Chinese herb new isolate isorhapontigenin (ISO) and mechanisms underlying its activity have never been explored. Here we demonstrated that ISO treatment with various concentrations for 3 weeks could dramatically inhibit TPA/EGF-induced cell transformation of Cl41 cells in Soft Agar assay, whereas co-incubation of cells with ISO at the same concentrations could elicit G0/G1 cell-cycle arrest without redundant cytotoxic effects on non-transformed cells. Further studies showed that ISO treatment resulted in cyclin D1 downregulation in dose- and time-dependent manner. Our results indicated that ISO regulated cyclin D1 at transcription level via targeting JNK/C-Jun/AP-1 activation. Moreover, we found that ISO-inhibited JNK/C-Jun/AP-1 activation was mediated by both upregulation of MKP-1 expression through increasing its mRNA stability and deactivating MKK7. Most importantly, MKP-1 knockdown could attenuate ISO-mediated suppression of JNK/C-Jun activation and cyclin D1 expression, as well as G0/G1 cell cycle arrest and cell transformation inhibition, while ectopic expression of FLAG-cyclin D1 T286A mutant also reversed ISO-induced G0/G1 cell-cycle arrest and inhibition of cell transformation. Our results demonstrated that ISO is a promising chemopreventive agent via upregulating mkp-1 mRNA stability, which is distinct from its cancer therapeutic effect with downregulation of XIAP and cyclin D1 expression.
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影响因子：
9
作者：
通讯作者：
--
DOI：
10.1038/nrc2646
发表时间：
2009-07
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.8
作者：
Fang, Yong;Yu, Yonghui;Huang, Chuanshu
通讯作者：
Huang, Chuanshu
影响因子：
--
作者：
Huang H;Ma L;Li J;Yu Y;Zhang D;Wei J;Jin H;Xu D;Gao J;Huang C
通讯作者：
Huang C
影响因子：
7.3
作者：
Abdelmohsen, Kotb;Gorospe, Myriam
通讯作者：
Gorospe, Myriam