The Role of Nrf2 Activity in Cancer Development and Progression (original) (raw)
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Cancer esearch or and Stem Cell Biology R zing Radiation Activates the Nrf 2 Antioxidant Response
2010
nloaded transcription factor NF-E2-related factor 2 (Nrf2) binds the antioxidant DNA response element (ARE) to te important cellular cytoprotective defense systems. Recently several types of cancers have been shown rexpress Nrf2, but its role in the cellular response to radiation therapy has yet to be fully determined. In udy, we report that single doses of ionizing radiation from 2 to 8 Gy activate ARE-dependent transcripbreast cancer cells in a dose-dependent manner, but only after a delay of five days. Clinically relevant ose fractions of radiation also increased ARE-dependent transcription, but again only after five days. stream activation of Nrf2-ARE-dependent gene and protein markers, such as heme oxygenase-1, oc, whereas Nrf2-deficient fibroblasts were incapable of these responses. Compared with wild-type fibro, Nrf2-deficient fibroblasts had relatively high basal levels of reactive oxygen species that increased five days after radiation exposure. Further, in vitro clonogenic...
Dual roles of NRF2 in tumor prevention and progression: Possible implications in cancer treatment
Free radical biology & medicine, 2015
The cap'n'collar (CNC) family serves as cellular sensors of oxidative and electrophilic stresses and shares structural similarities including basic leucine zipper (bZIP) and CNC domains. They form heterodimers with small MAF proteins to regulate antioxidant and phase II enzymes through antioxidant response element (ARE)-mediated transactivation. Among the CNC family members, NRF2 is required for systemic protection against redox-mediated injury and carcinogenesis. On the other hand, NRF2 is activated by oncogenic pathways, metabolism, and hypoxia. Constitutive NRF2 activation is observed in a variety of human cancers and it is highly correlated with tumor progression and aggressiveness. In this review, we will discuss how NRF2 plays dual roles in cancer prevention and progression depending on the cellular context and environment. Therefore, a better understanding of NRF2 will be necessary to exploit this complex network of balancing antioxidant pathways to inhibit tumor prog...
Cells, 2021
The gene expression program induced by NRF2 transcription factor plays a critical role in cell defense responses against a broad variety of cellular stresses, most importantly oxidative stress. NRF2 stability is fine-tuned regulated by KEAP1, which drives its degradation in the absence of oxidative stress. In the context of cancer, NRF2 cytoprotective functions were initially linked to anti-oncogenic properties. However, in the last few decades, growing evidence indicates that NRF2 acts as a tumor driver, inducing metastasis and resistance to chemotherapy. Constitutive activation of NRF2 has been found to be frequent in several tumors, including some lung cancer sub-types and it has been associated to the maintenance of a malignant cell phenotype. This apparently contradictory effect of the NRF2/KEAP1 signaling pathway in cancer (cell protection against cancer versus pro-tumoral properties) has generated a great controversy about its functions in this disease. In this review, we wil...
Journal of Cancer Research and Clinical Oncology, 2019
Purpose Tumor cells generally exhibit higher levels of reactive oxygen species (ROS), however, when stressed, tumor cells can undergo a process of 'Redox Resetting' to acquire a new redox balance with stronger antioxidant systems that enable cancer cells to become resistant to radiation therapy (RT). Here, we describe how RT affects the oxidant/antioxidant balance in human embryonal (RD) and alveolar (RH30) rhabdomyosarcoma (RMS) cell lines, investigating on the molecular mechanisms involved. Methods Radiations were delivered using an x-6 MV photon linear accelerator and their effects were assessed by vitality and clonogenic assays. The expression of specific antioxidant-enzymes, such as Superoxide Dismutases (SODs), Catalase (CAT) and Glutathione Peroxidases 4 (GPx4), miRNAs (miR-22,-126,-210,-375,-146a,-34a) and the transcription factor NRF2 was analyzed by quantitative polymerase chain reaction (q-PCR) and western blotting. RNA interference experiments were performed to evaluate the role of NRF2. Results Doses of RT higher than 2 Gy significantly affected RMS clonogenic ability by increasing ROS production. RMS rapidly and efficiently brought back ROS levels by up-regulating the gene expression of antioxidant enzymes, miRNAs as well as of NRF2. Silencing of NRF2 restrained the RMS ability to counteract RT-induced ROS accumulation, antioxidant enzyme and miRNA expression and was able to increase the abundance of γ-H2AX, a biomarker of DNA damage, in RT-treated cells. Conclusions Taken together, our data suggest the strategic role of oxidant/antioxidant balance in restraining the therapeutic efficiency of RT in RMS treatment and identify NRF2 as a new potential molecular target whose inhibition might represent a novel radiosensitizing therapeutic strategy for RMS clinical management.
The Dual Roles of NRF2 in Cancer
Trends in Molecular Medicine, 2016
NRF2 has been traditionally considered as a tumor suppressor because its cytoprotective functions are deemed to be the main cellular defense mechanism against exogenous and endogenous insults, including xenobiotics and oxidative stress. However, several recent studies demonstrate that hyperactivation of the NRF2 pathway creates an environment that favors the survival of normal as well as malignant cells, protecting them against oxidative stress, chemotherapeutic agents, and radiotherapy. In a rapidly advancing field, this review summarizes some of the known mechanisms by which NRF2 can exert its oncogenic functions, and describes the current status of NRF2 inhibitors, providing a clear rationale for the consideration of NRF2 as a powerful putative therapeutic target in cancer treatment. Trends Under homeostatic conditions, NRF2 activation prevents excessive cellular damage produced by metabolic, xenobiotic, and oxidative stress. NRF2 activation is thus important in cancer chemoprevention. Nrf2-null mice are more prone to develop cancer in response to chemical and physical stimuli (nitrosamine, ultraviolet light, aflatoxin). NRF2 hyperactivation confers several advantages to cancer cells, including protection from apoptosis and senescence, promotion of cell growth, and resistance to chemo-and radiotherapy. In experimental models, Nrf2/Keap1 mutations are present at pre-neoplastic stages. Distinct mechanisms are responsible for NRF2 activation in cancer, including (i) somatic mutations in NRF2 or KEAP1, (ii) epigenetic silencing of the KEAP1 promoter, (iii) microRNA-mediated regulation of NRF2 and KEAP1, (iv) aberrant accumulation of proteins that disrupt the interaction between NRF2 and KEAP1, (v) interaction with other 'cancer master players', and (vi) metabolic modifications.
Cancers, 2020
NF-E2 p45-related factor 2 (NRF2, encoded in the human by NFE2L2) mediates short-term adaptation to thiol-reactive stressors. In normal cells, activation of NRF2 by a thiol-reactive stressor helps prevent, for a limited period of time, the initiation of cancer by chemical carcinogens through induction of genes encoding drug-metabolising enzymes. However, in many tumour types, NRF2 is permanently upregulated. In such cases, its overexpressed target genes support the promotion and progression of cancer by suppressing oxidative stress, because they constitutively increase the capacity to scavenge reactive oxygen species (ROS), and they support cell proliferation by increasing ribonucleotide synthesis, serine biosynthesis and autophagy. Herein, we describe cancer chemoprevention and the discovery of the essential role played by NRF2 in orchestrating protection against chemical carcinogenesis. We similarly describe the discoveries of somatic mutations in NFE2L2 and the gene encoding the ...
Gain of Nrf2 Function in Non-Small-Cell Lung Cancer Cells Confers Radioresistance
Antioxidants & Redox Signaling, 2010
Nuclear factor erythroid-2 related factor 2 (Nrf2), a redox-sensitive transcription factor, regulates the expression of antioxidant enzymes and several anti-apoptotic proteins, which confer cytoprotection against oxidative stress and apoptosis. Constitutive activation of Nrf2 in lung cancer cells promotes tumorigenicity and contributes to chemoresistance by upregulation of glutathione, thioredoxin, and the drug efflux pathways involved in detoxification of electrophiles and broad spectrum of drugs. In this study, we show that RNAi-mediated lowering of Nrf2 levels in non-small-cell lung cancer (NSCLC) cell lines (A549 and H460) led to a dramatic increase in endogenous reactive oxygen species (ROS) levels. Similarly, g-irradiation-induced formation of protein carbonyls were significantly higher in Nrf2-depleted lung cancer cells, suggesting increased lethality of ionizing radiation in the absence of Nrf2. Radiation-induced protein oxidation in Nrf2shRNA cells correlated with reduced survival as measured by clonogenic assay. Radiation-induced cell death was abrogated by pretreatment with antioxidants such as N-acetyl-L-cysteine, glutathione, and vitamin-E, highlighting the importance of antioxidants in conferring protection against radiation injury. Using genetically-modified gain and loss of function models of Nrf2, in mouse embryonic fibroblasts, we establish that constitutive activation of Nrf2 protects against ionizing radiation toxicity and confers radioresistance. Thus, targeting Nrf2 activity in radioresistant tumors could be a promising strategy to circumvent radioresistance. Antioxid. Redox Signal. 13,
Ionizing Radiation Activates the Nrf2 Antioxidant Response
Cancer Research, 2010
The transcription factor Nrf2 binds the antioxidant DNA response element (ARE) to activate important cellular cytoprotective defense systems. Recently several types of cancers have been shown to overexpress Nrf2, but its role in the cellular response to radiation therapy has yet to be fully determined. In this study, we report that single doses of ionizing radiation from 2-8Gy activate AREdependent transcription in breast cancer cells in a dose-dependent manner, but only after a delay of 5 days. Clinically relevant daily dose fractions of radiation also increased ARE-dependent transcription, but again only after 5 days. Downstream activation occurred of Nrf2-ARE-dependent gene and protein markers, such as heme oxygenase-1, whereas Nrf2-deficient fibroblasts were incapable of these responses. Compared to wild-type fibroblasts, Nrf2-deficient fibroblasts had relatively high basal levels of reactive oxygen species that increased greatly five days after radiation exposure. Further, in vitro clonogenic survival assays and in vivo sublethal whole body irradiation tests demonstrated that Nrf2 deletion increased radiation sensitivity, whereas Nrf2-inducing drugs did not increase radioresistance. Our results indicate that the Nrf2-ARE pathway is important to maintain resistance to irradiation, but that it operates as a second-tier antioxidant adaptive response system activated by radiation only under specific circumstances, including those that may be highly relevant to tumor response during standard clinical dose-fractionated radiation therapy.
Perspectives of the Nrf-2 signaling pathway in cancer progression and therapy
Toxicology Reports, 2017
The Nuclear factor erythroid2-related factor2 (Nrf2), a master regulator of redox homoeostasis, is a key transcription factor regulating a wide array of genes for antioxidant and detoxification enzymes. It protects organs from various kinds of toxic insults. On the other hand, activation of Nrf2 is also correlated with cancer progression and chemoresistance. Downregulation of Nrf2 activity has attracted an increasing amount of attention as it may provide an alternative cancer therapy. In this review, we examine recent studies on roles of Nrf2 in several pathophysiological conditions emphasising cancer. We discuss elaborately the current knowledge on Nrf2 regulation including KEAP1-dependent and KEAP1-independent cascades. KEAP1/Nrf2 system is a master regulator of cellular response against a variety of environmental stresses. We also highlight several tightly controlled regulations of Nrf2 by numerous proteins, small molecules, toxic metals, etc. In addition, we evaluate the possible therapeutic approaches of increasing chemosensitivity via modulating Nrf2 signaling.
Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis
Nature, 2011
Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer 1 . Normally, ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors and is predominantly regulated by the transcription factor Nrf2 and its repressor protein Keap1 2-5 . In contrast to the acute physiological regulation of Nrf2, in neoplasia there is evidence for increased basal activation of Nrf2. Indeed, somatic mutations that disrupt the Nrf2-Keap1 interaction to stabilize Nrf2 and increase the constitutive transcription of Nrf2 target genes were recently identified, suggesting that enhanced ROS detoxification and additional Nrf2 functions may in fact be pro-tumorigenic 6 . Here, we investigated ROS metabolism in primary murine cells following the expression of endogenous oncogenic alleles of K-Ras, B-Raf and Myc, and find that ROS are actively suppressed by these oncogenes. K-Ras G12D , B-Raf V619E and Myc ERT2 each increased the transcription of Nrf2 to stably elevate the basal Nrf2 antioxidant program and thereby lower intracellular ROS and confer a more reduced intracellular environment. Oncogenedirected increased expression of Nrf2 is a novel mechanism for the activation of the Nrf2 antioxidant program, and is evident in primary cells and tissues of mice expressing K-Ras G12D and