Short interfering RNA-mediated silencing of glutaredoxin 2 increases the sensitivity of HeLa cells toward doxorubicin and phenylarsine oxide
Open accessAbstract
Glutaredoxin (Grx) belongs to the thioredoxin fold superfamily and catalyzes glutathione-dependent oxidoreductions. The recently discovered mitochondrial and nuclear Grx (Grx2) differs from the more abundant cytosolic Grx (Grx1) by its higher affinity toward S -glutathionylated proteins and by being a substrate for thioredoxin reductase. Here, we have successfully established a method to silence the expression of Grx2 in HeLa cells by using short interfering RNA to study its role in the cell. Cells with levels of Grx2 <3% of the control were dramatically sensitized to cell death induced by doxorubicin/adriamycin and phenylarsine oxide but did not show signs of a general increase in oxidative damage with respect to carbonylation and glutathionylation. The ED 50 for doxorubicin dropped from 40 to 0.7 μM and for phenylarsine oxide from 200 to 5 nM. However, no differences were detected after treatment with cadmium, a known inhibitor of Grx1. These results indicate a crucial role of Grx2 in the regulation of the mitochondrial redox status and regulation of cell death at the mitochondrial checkpoint.
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In cultured human cells, depletion of mitochondrial Grx2 increases cell sensitivity to apoptosis in response to agents causing oxidant stress.
“In cultured human cells, depletion of mitochondrial Grx2 was found to increase cell sensitivity to apoptosis in response to agents causing oxidant stress (255).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [255]
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- Authors
- Lillig, C. H., Lönn, M. E., Enoksson, M., Fernandes, A. P., & Holmgren, A.
- Affiliations
- Karolinska Institutet (SE)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-08-24
- Volume
- 101
- Issue
- 36
- Pages
- 13227-13232
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC516552
- OpenAlex
- W2122513194
- Cited by
- 147
- References
- 57
- Citations by year
- 2025: 3 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 9 · 2019: 4 · 2018: 4 · 2017: 4 · 2016: 6 · 2015: 8 · 2014: 5 · 2013: 8 · 2012: 4
- FWCI
- 4.02
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Keywords
- glutaredoxin 2, siRNA, gene silencing, doxorubicin, phenylarsine oxide, drug sensitivity, HeLa cells, mitochondrial redox status, cell death, glutathionylation, oxidative stress, cadmium
- MeSH terms
- Arsenicals, Cadmium, Doxorubicin, HeLa Cells, Humans, Oxidoreductases, Oxidative Stress, Gene Silencing, RNA, Small Interfering, Glutaredoxins
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