TrxR1 as a Potent Regulator of the Nrf2-Keap1 Response System

Cebula, Marcus; Schmidt, Edward E.; Arnér, Elias S.J.

doi:10.1089/ars.2015.6378

Cited by 208 publications

(167 citation statements)

References 335 publications

(245 reference statements)

Supporting

Mentioning

162

Contrasting

Order By: Relevance

“…In addition to the NF-kb signaling pathway, TrxR1 inhibition, either by auranofin or TrxR1-specific si/shRNA, has also been shown to induce an expression of the oxidative stress responsive transcription factor, Nrf2. 44,45 Moreover, Nrf2 activation has been shown to inhibit the NF-kb signaling pathway and attenuate NF-kb-mediated inflammatory responses and induce apoptosis. 46 Nrf2 deficient mouse embryonic fibroblasts showed activation of NF-kb, 47 suggesting that Nrf2 induction may inhibit the NF-kb signaling pathway in the cells.…”

Section: Discussionmentioning

confidence: 99%

TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

et al. 2016

View full text Add to dashboard Cite

Multiple myeloma (MM) is a B-cell malignancy characterized by an accumulation of abnormal clonal plasma cells in the bone marrow. Introduction of the proteasome-inhibitor bortezomib has improved MM prognosis and survival; however hypoxia-induced or acquired bortezomib resistance remains a clinical problem. This study highlighted the role of thioredoxin reductase 1 (TrxR1) in the hypoxia-induced and acquired bortezomib resistance in MM. Higher TrxR1 gene expression correlated with high-risk disease, adverse overall survival, and poor prognosis in myeloma patients. We demonstrated that hypoxia induced bortezomib resistance in myeloma cells and increased TrxR1 protein levels. Inhibition of TrxR1 using auranofin overcame hypoxia-induced bortezomib resistance and restored the sensitivity of hypoxicmyeloma cells to bortezomib. Hypoxia increased NF-kb subunit p65 nuclear protein levels and TrxR1 inhibition decreased hypoxia-induced NF-kb p65 protein levels in the nucleus and reduced the expression of NF-kb-regulated genes. In addition, higher TrxR1 protein levels were observed in bortezomib-resistant myeloma cells compared to the na€ ıve cells, and its inhibition using either auranofin or TrxR1-specific siRNAs reversed bortezomib resistance. TrxR1 inhibition reduced p65 mRNA and protein expression in bortezomib-resistant myeloma cells, and also decreased the expression of NF-kb-regulated anti-apoptotic and proliferative genes. Thus, TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance by inhibiting the NF-kb signaling pathway. Our findings demonstrate that elevated TrxR1 levels correlate with the acquisition of bortezomib resistance in MM. We propose considering TrxR1-inhibiting drugs, such as auranofin, either for single agent or combination therapy to circumvent bortezomibresistance and improve survival outcomes of MM patients.

show abstract

Section: Discussionmentioning

confidence: 99%

TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

et al. 2016

View full text Add to dashboard Cite

show abstract

“…A randomised clinical study of PDAC patients with advanced disease treated with thioredoxin inhibitor monotherapy failed to demonstrate improved outcomes, however considerable methodological issues may have obscured potential benefits of inhibiting this antioxidant system (Ramanathan et al, 2011). Interestingly, TrxR1 may also regulate Nrf2 activation (Cebula et al, 2015).…”

Section: The Effects Of Suppressing Nrf2 Compared To Nrf2/are Effectomentioning

confidence: 99%

Keap1–Nrf2 signalling in pancreatic cancer

Hayes

Skouras

Haugk

et al. 2015

The International Journal of Biochemistry & Cell Biology

View full text Add to dashboard Cite

a b s t r a c tTranscription factor NF-E2 p45-related factor 2 (Nrf2, also called Nfe2l2), a master regulator of redox homeostasis, and its dominant negative regulator, Kelch-like ECH-associated protein 1 (Keap1), together tightly control the expression of numerous detoxifying and antioxidant genes. Nrf2 and the 'antioxidant response element' (ARE)-driven genes it controls are frequently upregulated in pancreatic cancer and correlate with poor survival. Upregulation of Nrf2 is, at least in part, K-Ras oncogene-driven and contributes to pancreatic cancer proliferation and chemoresistance. In this review, we aim to provide an overview of Keap1-Nrf2 signalling as it relates to pancreatic cancer, discussing the effects of inhibiting Nrf2 or Nrf2/ARE effector proteins to increase chemosensitivity.

show abstract

“…Moreover, the antioxidants N-acetylcysteine (NAC) and vitamin E increase the proliferation of human lung cancer cells and tumor growth in mice with B-RAF-and K-RAS-induced lung cancer by reducing ROS, DNA damage, and p53 (7). These results suggest that lung tumor cells proliferate faster when the amounts of ROS are low, and this may be accomplished by dietary antioxidants or by mutations that activate an endogenous ROS defense system coordinated by NRF2/KEAP1 (8).…”

Section: Introductionmentioning

confidence: 99%

Antioxidants can increase melanoma metastasis in mice

et al. 2015

View full text Add to dashboard Cite

Antioxidants in the diet and supplements are widely used to protect against cancer, but clinical trials with antioxidants do not support this concept. Some trials show that antioxidants actually increase cancer risk and a study in mice showed that antioxidants accelerate the progression of primary lung tumors. However, little is known about the impact of antioxidant supplementation on the progression of other types of cancer, including malignant melanoma. We show that administration of N-acetylcysteine (NAC) increases lymph node metastases in an endogenous mouse model of malignant melanoma but has no impact on the number and size of primary tumors. Similarly, NAC and the soluble vitamin E analog Trolox markedly increased the migration and invasive properties of human malignant melanoma cells but did not affect their proliferation. Both antioxidants increased the ratio between reduced and oxidized glutathione in melanoma cells and in lymph node metastases, and the increased migration depended on new glutathione synthesis. Furthermore, both NAC and Trolox increased the activation of the small guanosine triphosphatase (GTPase) RHOA, and blocking downstream RHOA signaling abolished antioxidant-induced migration. These results demonstrate that antioxidants and the glutathione system play a previously unappreciated role in malignant melanoma progression.

show abstract

TrxR1 as a Potent Regulator of the Nrf2-Keap1 Response System

Abstract: Investigation of the role of TrxR1 as a regulator of Nrf2 activation will facilitate further studies of redox control in diverse cells and tissues of mammals, and possibly also in animals of other classes.

Cited by 208 publications

References 335 publications

TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

Keap1–Nrf2 signalling in pancreatic cancer

Antioxidants can increase melanoma metastasis in mice

Contact Info

Product

Resources

About