| Popis: |
STAT3 is a transcription factor involved in numerous 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 cancer, 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 STAT3 mitochondrial functions as tumor cells expressing only a mitochondrially-restricted form of STAT3 are highly sensitive to the compound, while STAT3-null cells are protected. OPB-51602 treatment abrogated complex I activity and led to mitophagy, actin skeletal rearrangements, and apoptosis. Cells undergoing reduced oxidative phosphorylation or expressing the NDI1 NADH dehydrogenase enzyme from Saccharomyces cerevisiae that bypasses mammalian complex I, were resistant to OPB-51602 toxicity. These results show that targeting mitochondrial STAT3 function causes a synthetic lethality involving complex I inhibition that could be exploited for cancer chemotherapy. |
