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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Inhibition of Hsp90 via 17-DMAG induces apoptosis in a p53-dependent manner to prevent medulloblastoma
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Inhibition of Hsp90 via 17-DMAG induces apoptosis in a p53-dependent manner to prevent medulloblastoma

机译：通过17-DMAG抑制Hsp90以p53依赖性方式诱导凋亡，以预防髓母细胞瘤

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摘要

Elevated expression of HSP90 is observed in many tumor types and is associated with a limited clinical response. Targeting HSP90 using inhibitors such as 17-DMAG (17-desmethoxy-17-N,N-dimeth-ylaminoethylaminogeldanamycin) has shown limited therapeutic success. HSP90 regulates the function of several proteins implicated in tumorigenesis although the precise mechanism through which 17-DMAG regulates tumor cell survival remains unclear. We observed a requirement for p53 in mediating 17-DMAG-induced cell death. The sensitivity of primary mouse embryonic fibroblasts and tumor cells to 17-DMAG-induced apoptosis depended on the p53 status. Wild-type MEFs underwent 17-DMAG-induced caspase-dependent cell death, whilst those lacking p53 failed to do so. Interestingly p53-dependent cell death occurred independently of Atm or Art. Primary tumor cells derived from two models of murine medulloblastoma (Ptch1~(+/-);lnk4c~(-/-) and p53~(FL/FL);Nestin-Cre~+; Ink4c~(-/-)) that retain and lack p53 function, respectively, displayed a dependence on functional p53 to engage 17-DMAG-induced apoptosis. Strikingly, 17-DMAG treatment in an allograft model of Ptch1~(+/-);lnk4c~(-/-) but not p53~(FL-FL);Nestin-Cre~+; Ink4c~(-/-) tumor cells prevented tumor growth in vivo. Our data suggest that p53 status is a likely predictor of the sensitivity of tumors to 17-DMAG.
机译：在许多肿瘤类型中观察到HSP90的表达升高，并且与有限的临床反应有关。使用抑制剂如17-DMAG（17-去甲氧基-17-N，N-二甲基-氨基氨基乙基氨基格尔德霉素）靶向HSP90已显示出有限的治疗成功。尽管尚不清楚17-DMAG调节肿瘤细胞存活的确切机制，但HSP90调节与肿瘤发生有关的几种蛋白质的功能。我们观察到介导17-DMAG诱导的细胞死亡需要p53。原代小鼠胚胎成纤维细胞和肿瘤细胞对17-DMAG诱导的细胞凋亡的敏感性取决于p53的状态。野生型MEF经历了17-DMAG诱导的caspase依赖性细胞死亡，而缺乏p53的则没有。有趣的是，p53依赖性细胞死亡独立于Atm或Art。源自鼠髓样母细胞瘤的两种模型（Ptch1〜（+/-）; lnk4c〜（-/-）和p53〜（FL / FL）; Nestin-Cre〜+; Ink4c〜（-/-））的原发性肿瘤细胞保留和缺乏p53功能分别显示出对功能性p53的依赖性，以参与17-DMAG诱导的细胞凋亡。引人注目的是，在同种异体移植的Ptch1〜（+/-）; lnk4c〜（-/-）而非p53〜（FL-FL）; Nestin-Cre〜+;的同种异体移植模型中进行17-DMAG处理。 Ink4c〜（-/-）肿瘤细胞阻止了体内肿瘤的生长。我们的数据表明，p53的状态可能是肿瘤对17-DMAG敏感性的预测指标。

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    Olivier Ayrault; Michael D. Godeny; Christopher Dillon; Frederique Zindy; Patrick Fitzgerald; Martine F. Roussel; Helen M. Beere;

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    Departments of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105;

    Departments of lmmunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105;

    Departments of lmmunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105;

    Departments of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105;

    Departments of lmmunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105;

    Departments of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105;

    Departments of lmmunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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