Abstract
The glutathione and thioredoxin pathways protect cells against ROS to promote tumorigenesis.
Major finding: The glutathione and thioredoxin pathways protect cells against ROS to promote tumorigenesis.
Clinical relevance: Dual targeting of the glutathione and thioredoxin pathways may be an effective therapeutic strategy.
Impact: Glutathione is required for tumor initiation, and inhibition of antioxidants may be chemopreventive.
Highly proliferative cancer cells are subjected to increased levels of reactive oxygen species (ROS), which have been shown to promote mutagenesis, suggesting that antioxidants such as glutathione (GSH) may prevent tumor formation. However, high levels of ROS induce oxidative stress, resulting in senescence and cell death, and recent studies have suggested that antioxidants instead protect cancer cells from ROS accumulation and enhance tumor progression. To further clarify the role of antioxidants in tumorigenesis, Harris and colleagues assessed the effects of inhibiting the GSH pathway on tumor initiation and progression. Genetic deletion of glutamate-cysteine ligase, modifier subunit (Gclm), which mediates GSH synthesis, impaired tumor initiation and progression in several mouse models of spontaneous tumor development. Similarly, early treatment with the GSH synthesis inhibitor buthionine-[S, R]-sulfoximine (BSO) prior to tumor development increased ROS levels and reduced tumor burden, indicating that ROS accumulation impairs malignant transformation and that GSH is required for tumor initiation. In contrast, administration of BSO after tumor onset did not affect ROS levels or diminish tumor burden, suggesting that alternate mechanisms may buffer ROS levels in established tumors. Consistent with this idea, Gclm-deficient cells exhibited increased expression of the antioxidant transcription factor nuclear factor (erythroid-derived 2)–like factor 2 (NFE2L2, also known as NRF2), which may compensate for decreased GSH synthesis to facilitate cell survival. In addition, inhibition of GSH synthesis increased intracellular cystine levels and expression of genes in the thioredoxin (TXN) antioxidant pathway, which were also upregulated in human breast cancers. Combined genetic or pharmacologic blockade of the GSH and TXN antioxidant pathways resulted in elevated ROS levels and synergistically increased cell death and reduced xenograft tumor growth in vivo. These results highlight a critical role for the GSH and TXN pathways in controlling ROS levels to enable tumor progression, and suggest that inhibition of antioxidant synthesis may be chemopreventive.
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