Genetic Manipulation of the Cellular Redox Environment Alters Oncogenic Phenotypes in Drosophila

The paradigm of antioxidants serving a protective role in cancer has shifted dramatically in recent years. Cancers often aberrantly express enzymes that control the redox environment and administration of antioxidants has been shown to accelerate the progression of some cancers. Research in model organisms like Drosophila have the advantage of precisely controlling the location and timing of gene expression that alters redox signaling. We genetically manipulated the levels of NRF2 and Keap1; two conserved master regulators of the cellular redox environment, while simultaneously overexpressing the oncogenes Src or Ras. We found that increasing antioxidant activity counters Ras- induced proliferation in stem cells and MAPK signaling in epithelial cells. We also found that decreased antioxidant activity promotes a Src-induced tumorigenic phenotype in adult flies. However, because the tumors formed in conjunction with reduced apoptosis rather than increased proliferation, this suggests that Src activity was likely mitigated with a lessening of antioxidant activity. Inhibiting antioxidants as a therapeutic approach to cancer is gaining momentum, therefore we hope that work in
Drosophila could serve as a powerful system to isolate discrete mechanisms regulated by redox signaling and subsequently, better inform treatment.