Prostate Cancer Discovery and Development Program, Philadelphia, Pennsylvania, USA.
J Clin Invest. 2011 Apr;121(4):1349-60. doi: 10.1172/JCI44855.
Fine tuning of the protein folding environment in subcellular organelles, such as mitochondria, is important for adaptive homeostasis and may participate in human diseases, but the regulators of this process are still largely elusive. Here, we have shown that selective targeting of heat shock protein-90 (Hsp90) chaperones in mitochondria of human tumor cells triggered compensatory autophagy and an organelle unfolded protein response (UPR) centered on upregulation of CCAAT enhancer binding protein (C/EBP) transcription factors. In turn, this transcriptional UPR repressed NF-κB-dependent gene expression, enhanced tumor cell apoptosis initiated by death receptor ligation, and inhibited intracranial glioblastoma growth in mice without detectable toxicity. These data reveal what we believe to be a novel role of Hsp90 chaperones in the regulation of the protein-folding environment in mitochondria of tumor cells. Disabling this general adaptive pathway could potentially be used in treatment of genetically heterogeneous human tumors.
细胞内细胞器（如线粒体）中蛋白质折叠环境的精细调节对于适应性稳态很重要，并且可能参与人类疾病，但这一过程的调节因子在很大程度上仍难以捉摸。在这里，我们已经表明，选择性靶向人肿瘤细胞线粒体中的热休克蛋白 90（Hsp90）伴侣蛋白会触发代偿性自噬和以 CCAAT 增强子结合蛋白（C/EBP）转录因子上调为中心的细胞器未折叠蛋白反应（UPR）。反过来，这种转录 UPR 抑制了 NF-κB 依赖性基因表达，增强了死亡受体配体引发的肿瘤细胞凋亡，并抑制了小鼠颅内神经胶质瘤的生长，而没有可检测到的毒性。这些数据揭示了我们认为 Hsp90 伴侣蛋白在调节肿瘤细胞线粒体中蛋白质折叠环境方面的一个新作用。使这种普遍的适应性途径失活可能会用于治疗遗传异质性的人类肿瘤。
