Brambilla Lara, Lahiri Tanaya, Cammer Michael, Levy David E
Department of Pathology, NYU Grossman School of Medicine, NYU Langone Health, 550 1st Avenue MSB548A, New York, NY 10016, USA.
Microscopy Core, Division of Advanced Research Technologies, NYU Grossman School of Medicine, 55- 1st Avenue SK2, New York, NY 10016, USA.
iScience. 2020 Nov 18;23(12):101822. doi: 10.1016/j.isci.2020.101822. eCollection 2020 Dec 18.
STAT3 is a transcription factor involved in several cellular activities including inflammation, proliferation, and survival, but it also plays a non-transcriptional role in modulating mitochondrial metabolism. Given its diverse functions in human cancers, it is an emerging therapeutic target. Here we show that OPB-51602, a small molecule inhibitor of STAT3, is highly toxic in a STAT3-dependent manner. Specifically, drug toxicity depends on mitochondrial STAT3 as tumor cells expressing only a mitochondrially restricted form of STAT3 are sensitive to the compound, whereas STAT3-null cells are protected. OPB-51602 inhibited complex I activity and led to increased ROS production, which in turn induced mitophagy, actin rearrangements, and cell death. Cells undergoing reduced oxidative phosphorylation or expressing NDI1 NADH dehydrogenase from , which bypasses mammalian complex I, were resistant to OPB-51602 toxicity. These results show that targeting mitochondrial STAT3 function causes synthetic lethality through complex I inhibition that could be exploited for cancer chemotherapy.
信号转导与转录激活因子3（STAT3）是一种转录因子，参与多种细胞活动，包括炎症、增殖和存活，但它在调节线粒体代谢中也发挥非转录作用。鉴于其在人类癌症中的多种功能，它是一个新兴的治疗靶点。在此我们表明，STAT3的小分子抑制剂OPB-51602以STAT3依赖性方式具有高毒性。具体而言，药物毒性取决于线粒体STAT3，因为仅表达线粒体限制性形式STAT3的肿瘤细胞对该化合物敏感，而STAT3缺失的细胞则受到保护。OPB-51602抑制复合体I的活性并导致活性氧生成增加，进而诱导线粒体自噬、肌动蛋白重排和细胞死亡。经历氧化磷酸化减少或表达来自酿酒酵母的NDI1 NADH脱氢酶（其绕过哺乳动物复合体I）的细胞对OPB-51602毒性具有抗性。这些结果表明，靶向线粒体STAT3功能通过抑制复合体I导致合成致死性，这可用于癌症化疗。
