Activation of the stress proteome as a mechanism for small molecule therapeutics

作者：Rebecca Deering Brose, Gloria Shin, Martina C. McGuinness, Tonya Schneidereith, Shirley H. Purvis, Gao X. Dong, Jeffrey R. Keefer, Forrest Spencer, Kirby D. Smith · 发表于：Human Molecular Genetics · 年份：2012 · DOI：10.1093/hmg/dds247 · 被引用次数：46 · 研究领域：Peroxisome Proliferator-Activated Receptors、RNA modifications and cancer、RNA regulation and disease

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 e...