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Thioredoxin Reductase Inhibition for Cancer Therapy
Radosveta Gencheva1, Elias S J Arnér1,2
1Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden;
Abstract:
The cytosolic selenoprotein thioredoxin reductase 1 (TrxR1, TXNRD1), and to some extent mitochondrial TrxR2 (TXNRD2), can be inhibited by a wide range of electrophilic compounds. Many such compounds also yield cytotoxicity toward cancer cells in culture or in mouse models, and most compounds are likely to irreversibly modify the easily accessible selenocysteine residue in TrxR1, thereby inhibiting its normal activity to reduce cytosolic thioredoxin (Trx1, TXN) and other substrates of the enzyme. This leads to an oxidative challenge. In some cases, the inhibited forms of TrxR1 are not catalytically inert and are instead converted to prooxidant NADPH oxidases, named SecTRAPs, thus further aggravating the oxidative stress, particularly in cells expressing higher levels of the enzyme. In this review, the possible molecular and cellular consequences of these effects are discussed in relation to cancer therapy, with a focus on outstanding questions that should be addressed if targeted TrxR1 inhibition is to be further developed for therapeutic use.
Insights
Electrophilic compounds inhibit thioredoxin reductase 1 (TrxR1), causing oxidative stress in cancer cells. Some TrxR1 inhibitors become prooxidant enzymes, worsening cancer therapy outcomes.
Area of Science:
- Biochemistry
- Cell Biology
- Cancer Research
Background:
- Thioredoxin reductase 1 (TrxR1) is a key enzyme in cellular redox homeostasis.
- Electrophilic compounds can inhibit TrxR1 and TrxR2, impacting cancer cell viability.
- Inhibition of TrxR1 can lead to oxidative stress and cytotoxicity.
Purpose of the Study:
- To review the molecular and cellular consequences of TrxR1 inhibition.
- To discuss the implications for cancer therapy.
- To identify key questions for the therapeutic development of TrxR1 inhibitors.
Main Methods:
- Literature review of studies on TrxR1 inhibition and cancer therapy.
- Analysis of molecular mechanisms of TrxR1 inhibition by electrophilic compounds.
- Discussion of cellular responses to TrxR1 inhibition, including oxidative stress and SecTRAP formation.
Main Results:
- Electrophilic compounds irreversibly inhibit TrxR1 by modifying its selenocysteine residue.
- TrxR1 inhibition leads to an oxidative challenge due to reduced thioredoxin activity.
- In some cases, inhibited TrxR1 forms prooxidant NADPH oxidases (SecTRAPs), exacerbating oxidative stress.
Conclusions:
- Targeted TrxR1 inhibition presents a potential cancer therapy strategy.
- Understanding the dual role of TrxR1 inhibitors (cytotoxic vs. prooxidant) is crucial.
- Further research is needed to address outstanding questions for effective therapeutic application of TrxR1 inhibition.
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