Thioredoxin reductase 1 knockdown disrupts pigment synthesis in melanocytes

Cassidy, Pamela B.; Kline, Chelsey D.; Carpenter, Evan L.; Laws, Madeleine; Moos, Philip J.; Indra, Arup K.; Leachman, Sancy A.

doi:10.1016/j.freeradbiomed.2018.10.131

Cited by 2 publications

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“…It was also reported that TrxR activity correlates with different skin phototypes I-VI (Fitzpatrick skin type system), where darker skin has significantly higher enzyme activity compared to very fair skin [74,75]. In addition, stable knockdown of TrxR1 resulted in a significant decrease in melanin levels and tyrosinase activity in melanocytes [76]. These studies suggested that high levels/activities of TrxR were correlated with melanin formation, providing additional information on the roles of cellular antioxidant proteins in melanogenesis (Table 1).…”

Section: The Thioredoxin System and Melanogenesismentioning

confidence: 93%

Modulating skin colour: role of the thioredoxin and glutathione systems in regulating melanogenesis

Tonissen

Trapani

2021

Bioscience Reports

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Different skin colour among individuals is determined by the varying amount and types of melanin pigment. Melanin is produced in melanocytes, a type of dendritic cell located in the basal layer of the epidermis, through the process of melanogenesis. Melanogenesis consists of a series of biochemical and enzymatic reactions catalysed by tyrosinase and other tyrosinase-related proteins, leading to the formation of two types of melanin, eumelanin and pheomelanin. Melanogenesis can be regulated intrinsically by several signalling pathways, including the cAMP/PKA, SCF/c-kit and Wnt/β-catenin signalling pathways. Ultraviolet radiation (UVR) is the major extrinsic factor in the regulation of melanogenesis, through the generation of reactive oxygen species (ROS). Antioxidants or antioxidant systems, with the ability to scavenge ROS, may decrease melanogenesis. This review focuses on the two main cellular antioxidant systems, the thioredoxin (Trx) and glutathione (GSH) systems, and discusses their roles in melanogenesis. In the Trx system, high levels/activities of thioredoxin reductase (TrxR) are correlated with melanin formation. The GSH system is linked with regulating pheomelanin formation. Exogenous addition of GSH has been shown to act as a depigmenting agent, suggesting that other antioxidants may also have the potential to act as depigmenting agents for the treatment of human hyperpigmentation disorders.

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Section: The Thioredoxin System and Melanogenesismentioning

confidence: 93%

Modulating skin colour: role of the thioredoxin and glutathione systems in regulating melanogenesis

Tonissen

Trapani

2021

Bioscience Reports

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“…TR1 knockdown and pharmacological inhibition of TRX lead to decreased melanin levels and reduced activity of tyrosinase, involved in melanin synthesis. TR1 knockdown also caused a delay in upregulation of the melanocyte transcriptional factor MITF [111]. TR is overexpressed in many cancer types and has been recognized as an anti-cancer target.…”

Section: Thioredoxin Systemmentioning

confidence: 99%

Redox-Related Proteins in Melanoma Progression

et al. 2022

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Melanoma is the most aggressive type of skin cancer. Despite the available therapies, the minimum residual disease is still refractory. Reactive oxygen and nitrogen species (ROS and RNS) play a dual role in melanoma, where redox imbalance is involved from initiation to metastasis and resistance. Redox proteins modulate the disease by controlling ROS/RNS levels in immune response, proliferation, invasion, and relapse. Chemotherapeutics such as BRAF and MEK inhibitors promote oxidative stress, but high ROS/RNS amounts with a robust antioxidant system allow cells to be adaptive and cooperate to non-toxic levels. These proteins could act as biomarkers and possible targets. By understanding the complex mechanisms involved in adaptation and searching for new targets to make cells more susceptible to treatment, the disease might be overcome. Therefore, exploring the role of redox-sensitive proteins and the modulation of redox homeostasis may provide clues to new therapies. This study analyzes information obtained from a public cohort of melanoma patients about the expression of redox-generating and detoxifying proteins in melanoma during the disease stages, genetic alterations, and overall patient survival status. According to our analysis, 66% of the isoforms presented differential expression on melanoma progression: NOS2, SOD1, NOX4, PRX3, PXDN and GPX1 are increased during melanoma progression, while CAT, GPX3, TXNIP, and PRX2 are decreased. Besides, the stage of the disease could influence the result as well. The levels of PRX1, PRX5 and PRX6 can be increased or decreased depending on the stage. We showed that all analyzed isoforms presented some genetic alteration on the gene, most of them (78%) for increased mRNA expression. Interestingly, 34% of all melanoma patients showed genetic alterations on TRX1, most for decreased mRNA expression. Additionally, 15% of the isoforms showed a significant reduction in overall patient survival status for an altered group (PRX3, PRX5, TR2, and GR) and the unaltered group (NOX4). Although no such specific antioxidant therapy is approved for melanoma yet, inhibitors or mimetics of these redox-sensitive proteins have achieved very promising results. We foresee that forthcoming investigations on the modulation of these proteins will bring significant advances for cancer therapy.

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Thioredoxin reductase 1 knockdown disrupts pigment synthesis in melanocytes

Cited by 2 publications

References 0 publications

Modulating skin colour: role of the thioredoxin and glutathione systems in regulating melanogenesis

Modulating skin colour: role of the thioredoxin and glutathione systems in regulating melanogenesis

Redox-Related Proteins in Melanoma Progression

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