Abstract
Increased production of mitochondrial-derived reactive oxygen species (ROS) is characteristic of a metabolic shift observed during malignant transformation. While the exact sources and roles of ROS in tumorigenesis remain to be defined, it has become clear that maintaining redox balance is critical for cancer cell proliferation and survival, and as such may represent a vulnerability that can be exploited therapeutically. STAT3, a latent cytosolic transcription factor activated by diverse cytokines and growth factors, has been shown to exhibit an additional, non-transcriptional function in mitochondria, including modulation of electron transport chain activity. In particular, malignant transformation by Ras oncogenes exploits mitochondrial STAT3 functions. We used mass-spectrometry based metabolomics profiling to explore the biochemical basis for the STAT3-dependence of Ras transformation. We identified the gamma-glutamyl cycle, the production of glutathione, and the regulation of ROS as a mitochondrial-STAT3 dependent pathway in Ras-transformed cells. Experimental inhibition of key enzymes in the gamma-glutamyl cycle resulted in depletion of glutathione, accumulation of ROS, oxidative DNA damage, and cell death in an oncogenic Ras and mitochondrial-STAT3 dependent manner. These data uncover a synthetic lethal interaction between electron transport chain activity, elevated mitochondrial ROS production, and glutathione abundance that are governed by mitochondrial STAT3 and might be exploited therapeutically.
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