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Review
. 2022 May 19:9:883297.
doi: 10.3389/fmolb.2022.883297. eCollection 2022.

The Role of the Thioredoxin Detoxification System in Cancer Progression and Resistance

Mirna Jovanović  1 , Ana Podolski-Renić  1 , Mikhail Krasavin  2 , Milica Pešić  1
Affiliations
Review

The Role of the Thioredoxin Detoxification System in Cancer Progression and Resistance

Mirna Jovanović et al. Front Mol Biosci. .

Abstract

The intracellular redox homeostasis is a dynamic balancing system between the levels of free radical species and antioxidant enzymes and small molecules at the core of cellular defense mechanisms. The thioredoxin (Trx) system is an important detoxification system regulating the redox milieu. This system is one of the key regulators of cells' proliferative potential as well, through the reduction of key proteins. Increased oxidative stress characterizes highly proliferative, metabolically hyperactive cancer cells, which are forced to mobilize antioxidant enzymes to balance the increase in free radical concentration and prevent irreversible damage and cell death. Components of the Trx system are involved in high-rate proliferation and activation of pro-survival mechanisms in cancer cells, particularly those facing increased oxidative stress. This review addresses the importance of the targetable redox-regulating Trx system in tumor progression, as well as in detoxification and protection of cancer cells from oxidative stress and drug-induced cytotoxicity. It also discusses the cancer cells' counteracting mechanisms to the Trx system inhibition and presents several inhibitors of the Trx system as prospective candidates for cytostatics' adjuvants. This manuscript further emphasizes the importance of developing novel multitarget therapies encompassing the Trx system inhibition to overcome cancer treatment limitations.

Keywords: RONS; Trx; TrxR; antioxidative defence; oxidative stress; resistance to therapy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The balance between RONS and the antioxidant defense system determines cell faith. The concentration of RONS is elevated in cancer cells, due to aberrant metabolism adjusted to accelerated growth and proliferation. To survive, cancer cells over-express enzymes of antioxidant defense. What’s more, RONS in cancer cells have an important part in tumor growth and promotion, in all stages of tumor development. However, further increase in RONS, by inhibition of the antioxidant detoxification systems, for example, causes cell death and inhibits tumor growth.
FIGURE 2
FIGURE 2
Redox systems ‐ Trx and GSH systems, are important regulators of intracellular RONS concentration. Major sources of RONS inside the cell are the electron transport chain (ETC) in mitochondria and NADPH oxidases (NOX). Superoxide anion (O2 −) is the main free-radical deriving from ETC; due to lack of stability, the molecule is relatively easily transmuted to hydrogen peroxide (H2O2) or peroxynitrite (ONOO−). Superoxide dismutase (SOD) is an enzyme catalyzing the transmutation of 2O− to H2O2. Further on, H2O2 is neutralized by several different enzymes and enzyme systems. The most potent is peroxiredoxins (Prx), a cysteine-dependent peroxidase that reacts with H2O2. Thioredoxin (Trx) reduces Prx, while thioredoxin reductase (TrxR) reduces oxidized Trx, with NADPH as an electron donor. Glutathione peroxidase (GPx) uses reduced glutathione (GSH) for neutralizing hydrogen peroxide. In turn, glutathione reductase (GR) reduces oxidized glutathione (GSSG), with NADPH as an electron donor. Another enzyme, involved in the regulation of H2O2 concentration, found mainly in peroxisomes and cytosol, is catalase (CAT).
FIGURE 3
FIGURE 3
The Trx system affects gene expression, apoptosis, proliferation, and oxidative and xenobiotics defense, through interactions with versatile executing proteins. Trx system comprises Trx, TrxR, and NADPH. TrxR reduces Trx, using NADPH as an electron donor. TXNIP inhibits Trx function in the cell. Trx affects the DNA binding affinity of transcription factors, such as AP1, p53, and NF-κB. Trx inhibits apoptosis-promoting protein ASK-1 and promotes proliferation through RNR activation. Trx reduces Prx, enabling it to provide antioxidant detoxification of peroxides inside the cell. Inhibitors of the Trx system are attractive targets for the development of novel anticancer drugs.
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