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.