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

• DOI: 10.1016/j.isci.2020.101822
• Publication Date: 2020-11-19T03:30:25Z
• Authors: Lara Brambilla; Tanaya Lahiri; Michael Cammer; David E. Levy
• Keywords: 0303 health sciences; 03 medical and health sciences; Science; Q; Cell Biology; Article; Cancer; 3. Good health

STAT3 is a transcription factor involved in several cellular activities including inflammation, proliferation, and survival, but it also plays non-transcriptional role modulating mitochondrial metabolism. Given its diverse functions human cancers, an emerging therapeutic target. Here we show that OPB-51602, small molecule inhibitor of STAT3, highly toxic STAT3-dependent manner. Specifically, drug toxicity depends on as tumor cells expressing only mitochondrially restricted form are sensitive to the compound, whereas STAT3-null protected. OPB-51602 inhibited complex I activity led increased ROS production, which turn induced mitophagy, actin rearrangements, cell death. Cells undergoing reduced oxidative phosphorylation or NDI1 NADH dehydrogenase from Saccharomyces cerevisiae, bypasses mammalian I, were resistant toxicity. These results targeting function causes synthetic lethality through inhibition could be exploited for cancer chemotherapy.