Poster Presentation 25th Lorne Cancer Conference 2013

Mitochondrial-STAT3 dependent regulation of glutathione synthesis is a tumour specific vulnerability. (#191)

Daniel Gough 1 , David E Levy 2
  1. Monash Institute of Medical Research, Clayton, Vic, Australia
  2. Experimental Pathology, New York University, New York, NY, USA
Mutations in the Ras oncogenes are observed in approximately 20% of cancers but despite the prevalence of these driving mutations there has been no success in developing targeted therapeutics. We recently found that a mitochondrial pool of STAT3 is required to support the altered metabolic state necessary for transformation by mutant H-, N- or K-Ras. The loss of STAT3 from non-transformed tissue does not alter survival, so, we hypothesized that targeting the activity of mitochondrial STAT3 will be an effective approach to treat Ras-driven tumours. To identify mitochondrial STAT3-dependent metabolic pathways required for Ras transformation, we performed a high throughput metabolomics screen. This screen identified the gamma-glutamyl cycle and its product glutathione as a pathway that was controlled by the mitochondrial pool of STAT3. Pharmacological inhibition of key enzymes in the gamma-glutamyl cycle lead to cell death in an oncogenic Ras and mitochondrial-STAT3 dependent manner.  Blockade of the gamma-glutamyl cycle leads to an increase in reactive oxygen species (ROS) which initiates cell death via the intrinsic apoptotic pathway. Moreover, decreasing the intracellular ROS concentration increases the tumourigenic potential of HRas transformed, STAT3-/- cells.  Together these data identify the gamma-glutamyl cycle as a potential therapeutic target in Ras transformation.