Redox Signaling and Nrf2 in Cancers

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 13609

Special Issue Editors


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Guest Editor
Laboratory for Oxidative Stress, Division of Molecular Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia
Interests: oxidative stress; reactive oxygen species (ROS); lipid peroxidation; cancer; cancer stem cells; cellular and extracellular antioxidants; Nrf2; metabolic reprogramming
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia
Interests: oxidative stress; antioxidative defense; lipid peroxidation; reactive oxygen species (ROS); cancer; cancer stem cells; aquaporins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are increasingly becoming aware of the importance of the role that redox signaling has today in both physiological and pathological processes. Switching specific protein-targets on and off ensures signal transduction, consequently orchestrating cellular fate. Reactive oxygen species (ROS), together with the thioredoxin, peroxiredoxin, and glutathione systems, are important in redox signaling. Nuclear factor erythroid 2-related factor 2 (NRF2), the major antioxidative transcription factor, is, among others, involved in the regulation of ROS levels and the components of the thioredoxin, peroxiredoxin, and glutathione systems. Therefore, investigating the role of ROS on one side and NRF2 in redox signaling is essential. Cancer is unquestionably a disease that is still challenging to cure, despite all the progression in the field. Combining the knowledge gained in cancer research together with the understanding of what the specific switches are and in what situations they occur in cancer redox signaling could open up new possibilities in cancer treatment, preventing its development and progression to metastasis formation.

For this Special Issue, we invite authors as well as the participants of The COST Action CA20121 to submit novel work or reviews establishing the importance of redox signaling and NRF2 in cancer development and progression. Possible implications in anticancer therapy are welcome as well. The topics include but are not limited to:

  • Redox signaling in cancer;
  • The NRF2 pathway in cancer;
  • ROS-induced specific protein modifications;
  • Involvement of the thioredoxin, peroxiredoxin, and glutathione systems in cancer;
  • Redox-modifying possibilities in anticancer treatment.
text

Dr. Lidija Milković
Dr. Ana Čipak Gašparović
Guest Editors

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Keywords

  • redox signaling
  • reactive oxygen species
  • cancer
  • nuclear factor erythroid 2-related factor 2 (NRF2)
  • intracellular antioxidant mechanisms

Published Papers (4 papers)

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Research

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25 pages, 7414 KiB  
Article
Distinct Roles of Nrf1 and Nrf2 in Monitoring the Reductive Stress Response to Dithiothreitol (DTT)
by Reziyamu Wufuer, Zhuo Fan, Jianxin Yuan, Ze Zheng, Shaofan Hu, Guiyin Sun and Yiguo Zhang
Antioxidants 2022, 11(8), 1535; https://doi.org/10.3390/antiox11081535 - 7 Aug 2022
Cited by 8 | Viewed by 2198
Abstract
Transcription factor Nrf2 (nuclear factor, erythroid 2-like 2, encoded by Nfe2l2) has been accepted as a key player in redox regulatory responses to oxidative or reductive stresses. However, relatively little is known about the potential role of Nrf1 (nuclear factor, erythroid 2-like [...] Read more.
Transcription factor Nrf2 (nuclear factor, erythroid 2-like 2, encoded by Nfe2l2) has been accepted as a key player in redox regulatory responses to oxidative or reductive stresses. However, relatively little is known about the potential role of Nrf1 (nuclear factor, erythroid 2-like 1, encoded by Nfe2l1) in the redox responses, particularly to reductive stress, although this ‘fossil-like’ factor is indispensable for cell homeostasis and organ integrity during the life process. Herein, we examine distinct roles of Nrf1 and Nrf2 in monitoring the defense response to 1,4–dithiothreitol (DTT, serving as a reductive stressor), concomitantly with unfolded protein response being induced by this chemical (also defined as an endoplasmic reticulum stressor). The results revealed that intracellular reactive oxygen species (ROS) were modestly increased in DTT-treated wild-type (WT) and Nrf1α−/− cell lines, but almost unaltered in Nrf2−/−ΔTA or caNrf2ΔN cell lines (with a genetic loss of transactivation or N-terminal Keap1-binding domains, respectively). This chemical treatment also enabled the rate of oxidized to reduced glutathione (i.e., GSSG to GSH) to be amplified in WT and Nrf2−/−ΔTA cells, but diminished in Nrf1α−/− cells, along with no changes in caNrf2ΔN cells. Consequently, Nrf1α−/−, but not Nrf2−/−ΔTA or caNrf2ΔN, cell viability was reinforced by DTT against its cytotoxicity, as accompanied by decreased apoptosis. Further experiments unraveled that Nrf1 and Nrf2 differentially, and also synergistically, regulated DTT-inducible expression of critical genes for defending against redox stress and endoplasmic reticulum stress. In addition, we also identified that Cys342 and Cys640 of Nrf1 (as redox-sensing sites within its N-glycodomain and DNA-binding domain, respectively) are required for its protein stability and transcription activity. Full article
(This article belongs to the Special Issue Redox Signaling and Nrf2 in Cancers)
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11 pages, 2016 KiB  
Article
Peroxiporins Are Induced upon Oxidative Stress Insult and Are Associated with Oxidative Stress Resistance in Colon Cancer Cell Lines
by Ana Čipak Gašparović, Lidija Milković, Claudia Rodrigues, Monika Mlinarić and Graça Soveral
Antioxidants 2021, 10(11), 1856; https://doi.org/10.3390/antiox10111856 - 22 Nov 2021
Cited by 11 | Viewed by 2787
Abstract
Oxidative stress can induce genetic instability and change cellular processes, resulting in colorectal cancer. Additionally, adaptation of oxidative defense causes therapy resistance, a major obstacle in successful cancer treatment. Peroxiporins are aquaporin membrane channels that facilitate H2O2 membrane permeation, crucial [...] Read more.
Oxidative stress can induce genetic instability and change cellular processes, resulting in colorectal cancer. Additionally, adaptation of oxidative defense causes therapy resistance, a major obstacle in successful cancer treatment. Peroxiporins are aquaporin membrane channels that facilitate H2O2 membrane permeation, crucial for regulating cell proliferation and antioxidative defense. Here, we investigated four colon cancer cell lines (Caco-2, HT-29, SW620, and HCT 116) for their sensitivity to H2O2, cellular antioxidative status, and ROS intracellular accumulation after H2O2 treatment. The expression of peroxiporins AQP1, AQP3, and AQP5 and levels of NRF2, the antioxidant transcription factor, and PPARγ, a transcription factor that regulates lipid metabolism, were evaluated before and after oxidative insult. Of the four tested cell lines, HT-29 was the most resistant and showed the highest expression of all tested peroxiporins and the lowest levels of intracellular ROS, without differences in GSH levels, catalase activity, nor NF2 and PPARγ levels. Caco-2 shows high expression of AQP3 and similar resistance as HT-29. These results imply that oxidative stress resistance can be obtained by several mechanisms other than the antioxidant defense system. Regulation of intracellular ROS through modulation of peroxiporin expression may represent an additional strategy to target the therapy resistance of cancer cells. Full article
(This article belongs to the Special Issue Redox Signaling and Nrf2 in Cancers)
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14 pages, 19638 KiB  
Article
NRF2 Mediates Therapeutic Resistance to Chemoradiation in Colorectal Cancer through a Metabolic Switch
by Séan M. O’Cathail, Chieh-Hsi Wu, Rachael Thomas, Maria A. Hawkins, Tim S. Maughan and Annabelle Lewis
Antioxidants 2021, 10(9), 1380; https://doi.org/10.3390/antiox10091380 - 28 Aug 2021
Cited by 8 | Viewed by 2711
Abstract
Radiation resistance is a significant clinical problem in rectal cancer treatment, the mechanisms of which are poorly understood. NRF2 signalling is known to contribute to chemo/radioresistance in some cancers, but its role in therapeutic resistance in colorectal cancer (CRC) is unexplored. Using siRNA [...] Read more.
Radiation resistance is a significant clinical problem in rectal cancer treatment, the mechanisms of which are poorly understood. NRF2 signalling is known to contribute to chemo/radioresistance in some cancers, but its role in therapeutic resistance in colorectal cancer (CRC) is unexplored. Using siRNA and CRiSPR/Cas9 isogenic CRC cell lines, we investigated the effect of the knockdown and upregulation of the NRF2 pathway on chemo-radiosensitivity. Poly (A) enriched RNA sequencing and geneset enrichment analysis (GSEA) were carried out on both sensitive and resistant cell models for mechanistic insights. Finally, a cohort of rectal patient samples was profiled to understand the clinical relevance of NRF2 signalling. Radioresistant cell lines were significantly radiosensitised by siRNA knockdown (SW1463, SER10 1.22, ANOVA p < 0.0001; HT55, SER10 1.17, ANOVA p < 0.01), but not the (already) radiosensitive HCT116. The constitutive activation of NRF2 via a CRISPR Cas9 NFE2L2 mutation, E79K, induced radioresistance in HCT116 (SER10 0.71, ANOVA, p < 0.0001). GSEA demonstrated significant opposing metabolic dependencies in NRF2 signalling, specifically, the downregulation of amino acid and protein synthesis with low levels of NRF2 and upregulation with over expression. In a clinical cohort of 127 rectal patients, using a validated mRNA signature, higher baseline NRF2 signalling was associated with incomplete responses to radiation higher final neoadjuvant rectal (NAR) score (OR 1.34, 95% C.I. 1.01–1.80, LRT p-value = 0.023), where high NAR indicates poor radiation response and poor long-term prognosis. This is the first demonstration of NRF2-mediated radiation resistance in colorectal cancer. NRF2 appears to regulate crucial metabolic pathways, which could be exploited for therapeutic interventions. Full article
(This article belongs to the Special Issue Redox Signaling and Nrf2 in Cancers)
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Review

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19 pages, 2071 KiB  
Review
Role of Nrf2 in Pancreatic Cancer
by Marta Cykowiak and Violetta Krajka-Kuźniak
Antioxidants 2022, 11(1), 98; https://doi.org/10.3390/antiox11010098 - 30 Dec 2021
Cited by 14 | Viewed by 4437
Abstract
Pancreatic tumors are a serious health problem with a 7% mortality rate worldwide. Inflammatory processes and oxidative stress play important roles in the development of pancreatic diseases/cancer. To maintain homeostasis, a balance between free radicals and the antioxidant system is essential. Nuclear Factor [...] Read more.
Pancreatic tumors are a serious health problem with a 7% mortality rate worldwide. Inflammatory processes and oxidative stress play important roles in the development of pancreatic diseases/cancer. To maintain homeostasis, a balance between free radicals and the antioxidant system is essential. Nuclear Factor Erythroid 2-Related Factor 2/NFE2L2 (Nrf2) and its negative regulator Kelch-Like ECH-Associated Protein 1 (Keap1) provide substantial protection against damage induced by oxidative stress, and a growing body of evidence points to the canonical and noncanonical Nrf2 signaling pathway as a pharmacological target in the treatment of pancreatic diseases. In this review, we present updated evidence on the activation of the Nrf2 signaling pathway and its importance in pancreatic cancer. Our review covers potential modulators of canonical and noncanonical pathway modulation mechanisms that may have a positive effect on the therapeutic response. Finally, we describe some interesting recent discoveries of novel treatments related to the antioxidant system for pancreatic cancer, including natural or synthetic compounds with therapeutic properties. Full article
(This article belongs to the Special Issue Redox Signaling and Nrf2 in Cancers)
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