Activation of the stress proteome as a mechanism for small molecule therapeutics
Activation of the stress proteome as a mechanism for small molecule therapeutics
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DOI：
10.1093/hmg/dds247
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发表时间：
2012-10-01
影响因子：
3.5
通讯作者：
Smith, Kirby D.
中科院分区：
文献类型：
--
作者：
Brose, Rebecca Deering;Shin, Gloria;Smith, Kirby D.
具有不同已知功能的各种小分子药物在不同的孟德尔和复杂疾病中产生相似的结果，表明它们可能诱导共同的细胞效应。这些分子包括组蛋白去乙酰化酶抑制剂，4-苯基丁酸酯（4PBA）和trichostatin A，以及两个没有直接组蛋白去乙酰化酶抑制剂活性的小分子，羟基脲（HU）和萝卜硫素。在某些情况下，组蛋白去乙酰化酶抑制剂的治疗效果归因于与致病基因相关的基因表达的增加。然而，本研究表明，线粒体生物发生的药理学诱导对于4PBA或HU在两种不同疾病模型（x连锁肾上腺脑白质营养不良和镰状细胞病）中的潜在治疗作用是必要的。我们假设对这四种分子的共同细胞反应是诱导线粒体生物发生和过氧化物酶体增殖和应激蛋白质组的激活，或适应性细胞生存反应。流式细胞术、免疫荧光和/或western分析显示，用这四种药物治疗人成纤维细胞可诱导线粒体和过氧化物酶体的生物发生。在处理过的正常人成纤维细胞中，所有四种药物在转录和翻译水平上诱导适应性细胞存活反应：热休克、未折叠蛋白、自噬和抗氧化反应以及c-jun n末端激酶途径。因此，激活进化上保守的应激蛋白质组和线粒体生物发生可能是对这种小分子治疗的共同细胞反应，也是各种疾病治疗作用的共同基础。调节这种新的治疗靶点可以扩大可治疗疾病的范围，而不直接针对致病的遗传异常。
Various small molecule pharmacologic agents with different known functions produce similar outcomes in diverse Mendelian and complex disorders, suggesting that they may induce common cellular effects. These molecules include histone deacetylase inhibitors, 4-phenylbutyrate (4PBA) and trichostatin A, and two small molecules without direct histone deacetylase inhibitor activity, hydroxyurea (HU) and sulforaphane. In some cases, the therapeutic effects of histone deacetylase inhibitors have been attributed to an increase in expression of genes related to the disease-causing gene. However, here we show that the pharmacological induction of mitochondrial biogenesis was necessary for the potentially therapeutic effects of 4PBA or HU in two distinct disease models, X-linked adrenoleukodystrophy and sickle cell disease. We hypothesized that a common cellular response to these four molecules is induction of mitochondrial biogenesis and peroxisome proliferation and activation of the stress proteome, or adaptive cell survival response. Treatment of human fibroblasts with these four agents induced mitochondrial and peroxisomal biogenesis as monitored by flow cytometry, immunofluorescence and/or western analyses. In treated normal human fibroblasts, all four agents induced the adaptive cell survival response: heat shock, unfolded protein, autophagic and antioxidant responses and the c-jun N-terminal kinase pathway, at the transcriptional and translational levels. Thus, activation of the evolutionarily conserved stress proteome and mitochondrial biogenesis may be a common cellular response to such small molecule therapy and a common basis of therapeutic action in various diseases. Modulation of this novel therapeutic target could broaden the range of treatable diseases without directly targeting the causative genetic abnormalities.