The thioredoxin system in cancer
Abstract
Thioredoxin (Trx), NADPH and thioredoxin reductase (TrxR) comprise a thioredoxin system which exists in nearly all living cells. It functions in thiol-dependent thiol-disulfide exchange reactions crucial to control of the reduced intracellular redox environment, cellular growth, defense against oxidative stress or control of apoptosis and has multi-facetted roles in mammalian cells including implications in cancer. Eg reduced Trx activates DNA binding of transcription factors and is involved in antioxidant defense through repair of oxidatively damaged proteins or as an electron donor to peroxiredoxins. The Trx system functions in synthesis of deoxyribonucleotides for DNA synthesis, both replication and repair, by ribonucleotide reductase. Trx and truncated Trx (Trx80) act in modulation of immune cell function. TrxR isoforms in the cytosol and the mitochondria are essential selenoenzymes with a selenocysteine in the active site. These enzymes display a remarkably broad substrate specificity but are also targets for existing chemotherapeutic drugs. Mammalian TrxR enzymes are linked to selenium metabolism as a result of being selenoproteins, but can also directly reduce low molecular selenium compounds like selenite and have been implicated in the chemoprevention effects of selenium against cancer. Numerous scientific reports describe higher expression of Trx and TrxR in some, but not all tumors. Some data suggest that high Trx could be linked to resistance to chemotherapies while others suggest that high Trx and TrxR may induce apoptosis and reduce the mitotic index of certain tumors linked to the p53 dependent cell death. Recent data suggest that TrxR is essential for the carcinogenic process and invasive phenotype of cancer. Both Trx and TrxR have been regarded as interesting targets for chemotherapy.
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Inhibition of Trx1 and Grx1 could have pro-apoptotic effects in cancer cells.
“Inhibition of Trx1 and Grx1 could, therefore, have pro-apoptotic effects in cancer cells23,29.”
From Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246 (2018) · cites this paper as [23]
The pro-inflammatory and anti-apoptotic properties of the Trx1 and Grx1 systems, as well as their redox capabilities, make them important for tumor cell survival.
“The pro-inflammatory and anti-apoptotic properties of the Trx1 and Grx1 systems, as well as their redox capabilities, make them important for tumor cell survival.”
From Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246 (2018) · cites this paper as [23]
The Trx1 and Grx1 systems are commonly upregulated in cancer cells to counteract oxidative stress from increased ROS production.
“The Trx1 and Grx1 systems are thus commonly upregulated in cancer cells to counteract the oxidative stress as a result of increased ROS production, which otherwise can lead to apoptosis or necrosis23.”
From Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246 (2018) · cites this paper as [23]
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Selenius, M., Rundlöf, A.-K., Olm, E., Fernandes, A. P., & Björnstedt, M. (2010) · Antioxidants & Redox Signaling · doi:10.1089/ars.2009.2884 · Cited by 170 · see citing works
Policastro, L. L., Ibañez, I. L., Notcovich, C., Duran, H. A., & Podhajcer, O. L. (2013) · Antioxidants & Redox Signaling · doi:10.1089/ars.2011.4367 · Cited by 120 · see citing works
Haffo, L., Lu, J., Bykov, V. J. N., Martin, S. S., Ren, X., Coppo, L., Wiman, K. G., & Holmgren, A. (2018) · Scientific Reports · doi:10.1038/s41598-018-31048-7 · Cited by 73 · see citing works
Self-citation
- Authors
- Arnér, E. S. J., & Holmgren, A.
- Affiliations
- Karolinska Institutet (SE)
- Corresponding author
- Arnér, Elias S.J.
- Venue
- Seminars in Cancer Biology
- Publisher
- Elsevier BV
- Published
- 2006-12
- Volume
- 16
- Issue
- 6
- Pages
- 420-426
- ISSN
- 1044-579X (ISSN-L)
- OpenAlex
- W2003675056
- Cited by
- 589
- References
- 93
- Citations by year
- 2026: 24 · 2025: 21 · 2024: 29 · 2023: 24 · 2022: 30 · 2021: 20 · 2020: 32 · 2019: 26 · 2018: 28 · 2017: 32 · 2016: 34 · 2015: 39 · 2014: 38 · 2013: 20 · 2012: 30
- FWCI
- 2.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Seminars in Cancer Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Keywords
- thioredoxin system, thioredoxin, thioredoxin reductase, cancer, redox homeostasis, thiol-disulfide exchange, selenoproteins, selenocysteine, selenium metabolism, chemoresistance, apoptosis, p53-dependent cell death, ribonucleotide reductase, DNA synthesis, oxidative stress, tumor invasion, chemotherapeutic target
- MeSH terms
- Humans, Neoplasms, Thioredoxins
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