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

Jovanović, Mirna; Podolski-Renić, Ana; Krasavin, Mikhail; Pešić, Milica

doi:10.3389/fmolb.2022.883297

Cited by 25 publications

(23 citation statements)

References 176 publications

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“…In this study we focused on TrxR1, regarded as one of the master regulators of cellular redox homeostasis, due to its central role in cytosolic H 2 O 2 detoxification. Elevated expression and/or activity of this protein has been observed in several cancers [ 23 ]. In the current study, high expression of TrxR1 both at the mRNA and protein level was detected in the majority of GBM patient group.…”

Section: Discussionmentioning

confidence: 99%

Menadione Potentiates Auranofin-Induced Glioblastoma Cell Death

Szeliga

Rola

2022

IJMS

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Glioblastoma (GBM) is the most aggressive primary brain tumor. Recently, agents increasing the level of oxidative stress have been proposed as anticancer drugs. However, their efficacy may be lowered by the cytoprotective activity of antioxidant enzymes, often upregulated in ne-oplastic cells. Here, we assessed the mRNA and protein expression of thioredoxin reductase 1 (TrxR1), a master regulator of cellular redox homeostasis, in GBM and non-tumor brain tissues. Next, we examined the influence of an inhibitor of TrxR1, auranofin (AF), alone or in combination with a prooxidant menadione (MEN), on growth of GBM cell lines, patient-derived GBM cells and normal human astrocytes. We detected considerable amount of TrxR1 in the majority of GBM tissues. Treatment with AF decreased viability of GBM cells and their potential to form colonies and neurospheres. Moreover, it increased the intracellular level of reactive oxygen species (ROS). Pre-treatment with ROS scavenger prevented the AF-induced cell death, pointing to the important role of ROS in the reduction of cell viability. The cytotoxic effect of AF was potentiated by treatment with MEN. In conclusion, our results identify TrxR1 as an attractive drug target and highlights AF as an off-patent drug candidate in GBM therapy.

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Section: Discussionmentioning

confidence: 99%

Menadione Potentiates Auranofin-Induced Glioblastoma Cell Death

Szeliga

Rola

2022

IJMS

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“…As mentioned above, redox signaling is essential for controlling cell fate by the Trx system [ 117 ], so it is not surprising that this system has been implicated in cancer biology [ 118 ]. Elevated expression of Trx/TrxR has been detected in multiple human tumor types such as breast, thyroid, prostate, and colorectal carcinoma, and melanoma where it is associated with aggressive behavior [ 74 , 119 ].…”

Section: Trx/trxr Functions In Health and Diseasementioning

confidence: 99%

The Thioredoxin System of Mammalian Cells and Its Modulators

Hasan

Tatarskiy

Shtil³

2022

Biomedicines

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Oxidative stress involves the increased production and accumulation of free radicals, peroxides, and other metabolites that are collectively termed reactive oxygen species (ROS), which are produced as by-products of aerobic respiration. ROS play a significant role in cell homeostasis through redox signaling and are capable of eliciting damage to macromolecules. Multiple antioxidant defense systems have evolved to prevent dangerous ROS accumulation in the body, with the glutathione and thioredoxin/thioredoxin reductase (Trx/TrxR) systems being the most important. The Trx/TrxR system has been used as a target to treat cancer through the thiol–disulfide exchange reaction mechanism that results in the reduction of a wide range of target proteins and the generation of oxidized Trx. The TrxR maintains reduced Trx levels using NADPH as a co-substrate; therefore, the system efficiently maintains cell homeostasis. Being a master regulator of oxidation–reduction processes, the Trx-dependent system is associated with cell proliferation and survival. Herein, we review the structure and catalytic properties of the Trx/TrxR system, its role in cellular signaling in connection with other redox systems, and the factors that modulate the Trx system.

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“…At the onset of cancer, it exhibits direct antioxidant properties by defending against nitro-oxidative stress caused by carcinogens and xenobiotics, along with the support of other antioxidant molecules/enzymes such as GSH, Prx, and Msr, thereby preventing cell malignancy and further metastasis. However, once tumor formation has initiated, elevated levels of Trx/TrxR relative to normal cells help in coping with elevated ROS levels and facilitate tumor progression and metastasis owing to their growth-promoting, apoptosis-resisting, and angiogenesis-supporting functions, implicating themselves as crucial harbingers of chemotherapeutic resistance [ 169 , 170 ]. Thus, many anticancer drugs, including the widely known auranofin, have been reportedly involved in research for testing their potencies against this robust antioxidant defense system in cancer cells [ 171 , 172 ].…”

Section: Drugs and Treatments: Current Potential And Challengesmentioning

confidence: 99%

S-Denitrosylation: A Crosstalk between Glutathione and Redoxin Systems

et al. 2022

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S-nitrosylation of proteins occurs as a consequence of the derivatization of cysteine thiols with nitric oxide (NO) and is often associated with diseases and protein malfunction. Aberrant S-nitrosylation, in addition to other genetic and epigenetic factors, has gained rapid importance as a prime cause of various metabolic, respiratory, and cardiac disorders, with a major emphasis on cancer and neurodegeneration. The S-nitrosoproteome, a term used to collectively refer to the diverse and dynamic repertoire of S-nitrosylated proteins, is relatively less explored in the field of redox biochemistry, in contrast to other covalently modified versions of the same set of proteins. Advancing research is gradually unveiling the enormous clinical importance of S-nitrosylation in the etiology of diseases and is opening up new avenues of prompt diagnosis that harness this phenomenon. Ever since the discovery of the two robust and highly conserved S-nitrosoglutathione reductase and thioredoxin systems as candidate denitrosylases, years of rampant speculation centered around the identification of specific substrates and other candidate denitrosylases, subcellular localization of both substrates and denitrosylases, the position of susceptible thiols, mechanisms of S-denitrosylation under basal and stimulus-dependent conditions, impact on protein conformation and function, and extrapolating these findings towards the understanding of diseases, aging and the development of novel therapeutic strategies. However, newer insights in the ever-expanding field of redox biology reveal distinct gaps in exploring the crucial crosstalk between the redoxins/major denitrosylase systems. Clarifying the importance of the functional overlap of the glutaredoxin, glutathione, and thioredoxin systems and examining their complementary functions as denitrosylases and antioxidant enzymatic defense systems are essential prerequisites for devising a rationale that could aid in predicting the extent of cell survival under high oxidative/nitrosative stress while taking into account the existence of the alternative and compensatory regulatory mechanisms. This review thus attempts to highlight major gaps in our understanding of the robust cellular redox regulation system, which is upheld by the concerted efforts of various denitrosylases and antioxidants.

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

Cited by 25 publications

References 176 publications

Menadione Potentiates Auranofin-Induced Glioblastoma Cell Death

Menadione Potentiates Auranofin-Induced Glioblastoma Cell Death

The Thioredoxin System of Mammalian Cells and Its Modulators

S-Denitrosylation: A Crosstalk between Glutathione and Redoxin Systems

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