Role of thioredoxin reductase 1 in dysplastic transformation of human breast epithelial cells triggered by chronic oxidative stress

Dong, Chunlan; Zhang, Lei; Sun, Ruoxuan; Liu, Jianying; Yin, Hong; Li, Xiaoxiao; Zheng, Xiaoqing

doi:10.1038/srep36860

Cited by 40 publications

(33 citation statements)

References 45 publications

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“…In several forms of cancer, TrxR1 expression and activity are used as diagnostic markers for early detection ( 8 , 39 ). As our data indicate, acetylation increases TrxR1 activity, and future work will include investigating TrxR1 acetylation as a potential diagnostic marker.…”

Section: Discussionmentioning

confidence: 99%

“…Overactive TrxR1 is associated with chemotherapeutic resistance, and TrxR1 activity is co-opted by cancer cells to defend against ROS generated by therapeutic compounds ( 35 ). TrxR1 activity levels are diagnostic for early detection of lung ( 39 ) and breast cancers ( 8 ), and TrxR1 has emerged as a target to combat drug-resistant lung cancers, for example, ethaselen ( 49 ). In mouse models of age-related macular degeneration and glaucoma, overexpression of amyloid β was associated with increased TrxR1 activity despite unperturbed TrxR1 protein abundance, implicating post-translational modifications in regulating TrxR1 activity ( 25 ).…”

Section: Introductionmentioning

confidence: 99%

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Acetylation Regulates Thioredoxin Reductase Oligomerization and Activity

Wright

Altaany

et al. 2018

Antioxidants & Redox Signaling

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Aims: Thioredoxin reductase 1 (TrxR1) is a cancer target and essential selenoprotein that defends the cell against reactive oxygen species and regulates cellular signaling and redox pathways. Previous cell-based studies correlated TrxR1 acetylation with modulated cellular reduction activity, yet the function of specific acetylation sites on TrxR1 remains unknown.Innovation: We produced site-specifically acetylated TrxR1 variants that also contain selenocysteine (Sec). We demonstrated efficient high-fidelity protein synthesis with 22 different amino acids by simultaneous UAG codon reassignment to Nɛ-acetyl-lysine and UGA codon recoding to Sec.Results: We characterized TrxR1 variants acetylated at physiologically relevant sites and found that single acetylation sites increased TrxR1 activity, enhancing the apparent catalytic rate up to 2.7-fold. The activity increase in acetylated TrxR1 (acTrxR1) is reversible and is reduced following deacetylation with histone deacetylase.Conclusion: Here we present a novel mechanism through which acetylation increases TrxR1 activity by destabilizing low-activity TrxR1 multimers, increasing the population of active dimeric TrxR1. Antioxid. Redox Signal. 29, 377–388.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Acetylation Regulates Thioredoxin Reductase Oligomerization and Activity

Wright

Altaany

et al. 2018

Antioxidants & Redox Signaling

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“…Thus, the newly identified miR-23 mediated regulatory mechanism is likely to take part, with other classes of molecules (i.e CPEB, or AREs binding proteins) in the complex post-transcriptional regulation acting on TrxR1 expression via its 3′UTR. Moreover, given the relevance of TrxR1 in several human diseases including cancer 37 , 38 , the identification of a novel mechanism which can modulate its expression may open new interesting perspectives.…”

Section: Discussionmentioning

confidence: 99%

MiR-23-TrxR1 as a novel molecular axis in skeletal muscle differentiation

Neri

Fittipaldi

Paola

et al. 2017

Sci Rep

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Thioredoxin reductase 1 (TrxR1) is a selenocysteine-containing protein involved in cellular redox homeostasis which is downregulated in skeletal muscle differentiation. Here we show that TrxR1 decrease occurring during myogenesis is functionally involved in the coordination of this cellular process. Indeed, TrxR1 depletion reduces myoblasts growth by inducing an early myogenesis -related gene expression pattern which includes myogenin and Myf5 up-regulation and Cyclin D1 decrease. On the contrary, the overexpression of TrxR1 during differentiation delays myogenic process, by negatively affecting the expression of Myogenin and MyHC. Moreover, we found that miR-23a and miR-23b - whose expression was increased in the early stage of C2C12 differentiation - are involved in the regulation of TrxR1 expression through their direct binding to the 3′ UTR of TrxR1 mRNA. Interestingly, the forced inhibition of miR-23a and miR-23b during C2C12 differentiation partially rescues TrxR1 levels and delays the expression of myogenic markers, suggesting the involvement of miR-23 in myogenesis via TrxR1 repression. Taken together, our results depict for the first time a novel molecular axis, which functionally acts in skeletal muscle differentiation through the modulation of TrxR1 by miR-23.

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“…Mammalian thioredoxin reductase system (TrxR) plays a crucial role in regulating the multiple redox based signaling pathways and have attracted increased attention in designing the cancer drug targets 26 , 49 – 51 . Enhanced expression of TxrR1 has been observed in many primary tumors, suggesting that tumor cells are adapted to survive and proliferate 52 , 53 . Hence, we investigated the underlying mechanism of ROS accumulation by monitoring the protein expression of both Trx1 and TrxR1.…”

Section: Discussionmentioning

confidence: 99%

β-Sitosterol targets Trx/Trx1 reductase to induce apoptosis in A549 cells via ROS mediated mitochondrial dysregulation and p53 activation

Rajavel

Packiyaraj

Venkatesan

et al. 2018

Sci Rep

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β-Sitosterol (BS), a major bioactive constituent present in plants and vegetables has shown potent anticancer effect against many human cancer cells, but the underlying mechanism remain elusive on NSCLC cancers. We found that BS significantly inhibited the growth of A549 cells without harming normal human lung and PBMC cells. Further, BS treatment triggered apoptosis via ROS mediated mitochondrial dysregulation as evidenced by caspase-3 & 9 activation, Annexin-V/PI positive cells, PARP inactivation, loss of MMP, Bcl-2-Bax ratio alteration and cytochrome c release. Moreover, generation of ROS species and subsequent DNA stand break were found upon BS treatment which was reversed by addition of ROS scavenger (NAC). Indeed BS treatment increased p53 expression and its phosphorylation at Ser15, while silencing the p53 expression by pifithrin-α, BS induced apoptosis was reduced in A549 cells. Furthermore, BS induced apoptosis was also observed in NCI-H460 cells (p53 wild) but not in the NCI-H23 cells (p53 mutant). Down-regulation of Trx/Trx1 reductase contributed to the BS induced ROS accumulation and mitochondrial mediated apoptotic cell death in A549 and NCI-H460 cells. Taken together, our findings provide evidence for the novel anti-cancer mechanism of BS which could be developed as a promising chemotherapeutic drug against NSCLC cancers.

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Role of thioredoxin reductase 1 in dysplastic transformation of human breast epithelial cells triggered by chronic oxidative stress

Cited by 40 publications

References 45 publications

Acetylation Regulates Thioredoxin Reductase Oligomerization and Activity

Acetylation Regulates Thioredoxin Reductase Oligomerization and Activity

MiR-23-TrxR1 as a novel molecular axis in skeletal muscle differentiation

β-Sitosterol targets Trx/Trx1 reductase to induce apoptosis in A549 cells via ROS mediated mitochondrial dysregulation and p53 activation

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