Institut für Pharmazie und Molekulare Biotechnologie, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany.
Department of Organismal Biology, Uppsala University, Uppsala, S-75236, Sweden.
Sci Rep. 2017 Nov 13;7(1):15388. doi: 10.1038/s41598-017-15342-4.
Stat3 is an oncogene, frequently associated with malignant transformation. A body of evidence implicates that phospho-Stat3 contributes to its nucleic translocation, while phospho-Stat3 leads to the accumulation in mitochondria. Both are of importance for tumor cell proliferation. In comparison to well-characterized signaling pathways interplaying with Stat3, little is known about Stat3. In this work, we studied the influence of Stat3 deficiency on the viability of cells exposed to HO or hypoxia using siRNA and CRISPR/Cas9 genome-editing. We found dysregulation of mitochondrial activity, which was associated with excessive ROS formation and reduced mitochondrial membrane potential, and observed a synergistic effect for oxidative stress-mediated apoptosis in Stat3-KD cells or cells carrying Stat3, but not Stat3, suggesting the importance of functional mitochondrial Stat3 in this context. We also found that ROS-mediated activation of ASK1/p38 was involved and adding antioxidants, p38 inhibitor, or genetic repression of ASK1 could easily rescue the cellular damage. Our finding reveals a new role of mitochondrial Stat3 in preventing ASK1/p38-mediated apoptosis, wich further support the notion that selective inhibition mitochondrial Stat3 could provide a primsing target for chemotherapy.
Stat3 是一种癌基因，常与恶性转化有关。有大量证据表明，磷酸化 Stat3 有助于其核易位，而磷酸化 Stat3 导致其在线粒体中积累。这两者对于肿瘤细胞的增殖都很重要。与已充分研究的与 Stat3 相互作用的信号通路相比，对 Stat3 的了解甚少。在这项工作中，我们使用 siRNA 和 CRISPR/Cas9 基因组编辑研究了 Stat3 缺乏对 HO 或缺氧暴露的细胞活力的影响。我们发现线粒体活性失调，这与过多的 ROS 形成和线粒体膜电位降低有关，并观察到 Stat3-KD 细胞或携带 Stat3 但不是 Stat3 的细胞中氧化应激介导的细胞凋亡具有协同作用，这表明在这种情况下功能性线粒体 Stat3 的重要性。我们还发现 ROS 介导的 ASK1/p38 的激活参与其中，添加抗氧化剂、p38 抑制剂或 ASK1 的基因抑制可以很容易地挽救细胞损伤。我们的发现揭示了线粒体 Stat3 在防止 ASK1/p38 介导的细胞凋亡中的新作用，这进一步支持了选择性抑制线粒体 Stat3 可能为化疗提供有希望的靶标的观点。
