STAT3 Inhibitor OPB-51602 Is Cytotoxic to Tumor Cells Through Inhibition of Complex I and ROS Induction

iScience

Tanaya Lahiri¹  David E. Levy¹  Lara Brambilla¹  Michael Cammer² 

[1] 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;

关键词: Cell Biology;    Cancer;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: 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 Saccharomyces cerevisiae, 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.

【 授权许可】

Unknown