Gene and protein expression profiling of human ovarian cancer cells treated with the heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin
Gene and protein expression profiling of human ovarian cancer cells treated with the heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin
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DOI：
10.1158/0008-5472.can-06-2968
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发表时间：
2007-04-01
期刊：
影响因子：
11.2
通讯作者：
Workman, Paul
中科院分区：
文献类型：
--
作者：
Maloney, Alison;Clarke, Paul A.;Workman, Paul
17-烯丙基氨基-17-去甲氧基格尔德霉素（17-allylamino-17-demethoxygeldanamycin，17 AAG）的抗肿瘤活性是通过抑制分子伴侣热休克蛋白90（HSP 90）和随后降解多种致癌客户蛋白来实现的。应用基因表达谱芯片和蛋白质组学分析技术，研究了17-AAG处理后A2780人卵巢癌细胞系的分子变化。与非活性类似物和替代性HSP 90抑制剂根赤霉素的结果比较表明，在mRNA水平上增加HSP 72、HSC 70、HSP 27、HSP 47和HSP 9013的表达是17 AAG的靶向效应。用17 AAG治疗后，肿瘤活检组织中的HSP 27蛋白水平增加。一组MYC调节的mRNA被17 AAG降低。特别感兴趣的和新奇的是染色质相关蛋白的表达的变化。异染色质蛋白I的表达增加，并且历史乙酰转移酶I和组蛋白精氨酸甲基转移酶PRMT 5的表达被17 AAG降低。PRMT 5被证明是一种新的HSP 90结合伴侣和潜在的客户蛋白。17 AAG可减少细胞蛋白质乙酰化，研究表明17 AAG与组蛋白脱乙酰酶抑制剂曲古抑菌素A对细胞增殖具有拮抗作用。这种mRNA和蛋白质表达分析为17 AAG的复杂分子药理学提供了新的见解，并提出了可能参与药物反应或成为药物作用的潜在生物标志物的新基因和蛋白质。
The promising antitumor activity of 17-allylamino-17-demethoxygeldanamycin (17AAG) results from inhibition of the molecular chaperone heat shock protein 90 (HSP90) and subsequent degradation of multiple oncogenic client proteins. Gene expression microarray and proteomic analysis were used to profile molecular changes in the A2780 human ovarian cancer cell line treated with 17AAG. Comparison of results with an inactive analogue and an alternative HSP90 inhibitor radicicol indicated that increased expression of HSP72, HSC70, HSP27, HSP47, and HSP9013 at the mRNA level were on-target effects of 17AAG. HSP27 protein levels were increased in tumor biopsies following treatment of patients with 17AAG. A group of MYC-regulated mRNAs was decreased by 17AAG. Of particular interest and novelty were changes in expression of chromatin-associated proteins. Expression of the heterochromatin protein I was increased, and expression of the historic acetyltransferase I and the histone arginine methyltransferase PRMT5 was decreased by 17AAG. PRMT5 was shown to be a novel HSP90-binding partner and potential client protein. Cellular protein acetylation was reduced by 17AAG, which was shown to have an antagonistic interaction on cell proliferation with the histone deacetylase inhibitor trichostatin A. This mRNA and protein expression analysis has provided new insights into the complex molecular pharmacology of 17AAG and suggested new genes and proteins that may be involved in response to the drug or be potential biomarkers of drug action.