Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression.

By I. Harris, A. Treloar, S. Inoue, M. Sasaki, C. Gorrini, Kim-Chung Lee, K. Yung, D. Brenner, C. Knobbe-Thomsen, M. Cox and 16 more. Cancer Cell, 2015

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Controversy 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.

Subfields: Biochemistry, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/09f169c0ac46feb210a795363ecac8f27dd52e1e

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Citations in the corpus

Mechanisms of ferroptosis (2016, background): “For example, high levels of SLC7A11-mediated Cys 2 import, in conjunction with the GSH-in-dependent thioredoxin (Txn) system, can substitute for the essential function of the GSH-GPX4 lipid peroxide metabolic pathway in some cells both in vitro and in vivo [42–44].”
Targeting Metabolism for Cancer Therapy (2017, background): “, 2006), and genetic or pharmacological inhibition of glutathione synthesis results in ROS accumulation and impedes cancer initiation and cell proliferation (Harris et al., 2015; Lien et al., 2016).”
Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy (2022, background): “Nevertheless, some cancers are inevitably resistant to sorafenib, which may be caused by the upregulation of the non-GSH-dependent thioredoxin antioxidant pathway.(370,371) Conversely, octreotide, which is FDA-approved for ovarian cancer treatment, can directly target and inhibit GPX4 to induce ferr”
Fundamentals of cancer metabolism (2016, background): “Therefore, inactivating NRF2 or disabling antioxidant proteins in cancer cells would allow for the accumulation of excessive amounts of ROS to levels that initiate toxicity and reduce tumorigenesis (128, 131, 132).”
Oxidative Stress in Cancer (2020, background): “cancer cell death, implying roles for these complementary antioxidants in therapeutic intervention (Harris et al., 2015).”
Role of Glutathione in Cancer: From Mechanisms to Therapies (2020, background): “Through its many physiological functions (Figure 4) glutathione has a major role in tumors with a number of publications showing that increased cellular levels of glutathione are necessary for tumor initiation and proliferation [48,49].”
Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease (2015, positive): “Support for this hypothesis comes from the finding that knockout of the Nrf2-target gene Gclm in mice decreases GSH levels to just 20% with respect to wild-type mice and this is sufficient to prevent malignant transformation in murine tumorigenesis models, including mammary cancer produced in MMTV-P”