Glutathione and Thioredoxin Antioxidant Pathways Synergize to Drive Cancer Initiation and Progression

• The GSH antioxidant pathway is required for cancer initiation
• After cancer initiation, GSH is dispensable due to alternative antioxidant pathways
• The TXN antioxidant pathway is upregulated in tumors
• Inhibition of both GSH and TXN pathways causes synergistic cancer cell death

SummaryControversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer initiation. Genetic loss of Gclm prevents a tumor’s ability to drive malignant transformation. Intriguingly, these findings can be replicated using an inhibitor of GSH synthesis, but only if delivered prior to cancer onset, suggesting that at later stages of tumor progression GSH becomes dispensable potentially due to compensation from alternative antioxidant pathways. Remarkably, combined inhibition of GSH and thioredoxin antioxidant pathways leads to a synergistic cancer cell death in vitro and in vivo, demonstrating the importance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention.

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