Naturally occurring small-molecule inhibitors of hedgehog/GLI-mediated transcription
Naturally occurring small-molecule inhibitors of hedgehog/GLI-mediated transcription
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DOI：
10.1002/cbic.200700511
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发表时间：
2008-05-05
期刊：
影响因子：
3.2
通讯作者：
Ishibashi, Masami
中科院分区：
文献类型：
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作者：
Hosoya, Takahiro;Arai, Midori A.;Ishibashi, Masami
异常的hedgehog (Hh)/GLI信号通路导致多种肿瘤的形成和发展。为了寻找Hh/GLI抑制剂，我们使用基于细胞的试验筛选转录激活因子GLI1的天然抑制剂。我们鉴定了zerumbone(1)、zerumbone环氧化物(2)、staurosporinone(9)、6- hydroxyousrosporinone（10）、orcyri黄素C（71）和5,6- dihydroxyyarcyrioflovin A（12）作为gli介导的转录抑制剂。此外，我们还从最小Physalis中分离出了同样是有效抑制剂的physolins F（17）和B（18）。这些化合物也抑制gli2介导的转激活。半定量RT-PCR和Western blotting分析进一步发现，1、9、17和18降低了hh相关成分的表达。我们还发现，glii介导的转激活抑制剂可降低抗凋亡BcI2的表达水平。最后，这些鉴定的化合物对表达Hh/GLI成分的PANC1胰腺癌细胞具有细胞毒性。这些结果强烈表明，化合物对PANC1细胞的细胞毒性与它们对glii介导的转录的抑制有关。
The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. To search for Hh/GLI inhibitors, we screened for naturally occurring inhibitors of the transcriptional activator GLI1 by using a cell-based assay. We identified zerumbone (1), zerumbone epoxide (2), staurosporinone (9), 6-hydroxystourosporinone (10), orcyriaflavin C (71) and 5,6-dihydroxyarcyrioflovin A (12) as inhibitors of GLI-mediated transcription. In addition, we isolated physolins F (17) and B (18) from Physalis minima, which are also potent inhibitors. These compounds also inhibited GLI2-mediated transactivation. Semiquantitative RT-PCR and Western blotting analysis further revealed that 1, 9, 17, and 18 decreased Hh-related component expressions. We also show that inhibitors of GLI-mediated transactivation reduce the level of the antiapoptosis BcI2 expression. Finally, these identified compounds were cytotoxic to PANC1 pancreatic cancer cells, which express Hh/GLI components. These results strongly suggest that the cytotoxicity of the compounds to PANC1 cells correlates with their inhibition of GLI-mediated transcription.