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Journal ArticleDOI

The emerging role of the Nrf2–Keap1 signaling pathway in cancer

15 Oct 2013-Genes & Development (Cold Spring Harbor Laboratory Press)-Vol. 27, Iss: 20, pp 2179-2191
TL;DR: The studies suggest that Nrf2 contributes to both intrinsic and acquired chemoresistance, and the challenges in the development of NRF2-based drugs for chemoprevention and chemotherapy are outlined.
Abstract: The Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2 [Nrf2])-Keap1 (Kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1) signaling pathway is one of the most important cell defense and survival pathways. Nrf2 can protect cells and tissues from a variety of toxicants and carcinogens by increasing the expression of a number of cytoprotective genes. As a result, several Nrf2 activators are currently being tested as chemopreventive compounds in clinical trials. Just as Nrf2 protects normal cells, studies have shown that Nrf2 may also protect cancer cells from chemotherapeutic agents and facilitate cancer progression. Nrf2 is aberrantly accumulated in many types of cancer, and its expression is associated with a poor prognosis in patients. In addition, Nrf2 expression is induced during the course of drug resistance. Collectively, these studies suggest that Nrf2 contributes to both intrinsic and acquired chemoresistance. This discovery has opened up a broad spectrum of research geared toward a better understanding of the role of Nrf2 in cancer. This review provides an overview of (1) the Nrf2-Keap1 signaling pathway, (2) the dual role of Nrf2 in cancer, (3) the molecular basis of Nrf2 activation in cancer cells, and (4) the challenges in the development of Nrf2-based drugs for chemoprevention and chemotherapy.

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Journal ArticleDOI
TL;DR: It is argued that redox biology, rather than oxidative stress, underlies physiological and pathological conditions.

4,297 citations

Journal ArticleDOI
TL;DR: A conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis will progressively support the development of new strategies to treat human cancer.
Abstract: Tumors reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells. These reprogrammed activities are now recognized as hallmarks of cancer, and recent work has uncovered remarkable flexibility in the specific pathways activated by tumor cells to support these key functions. In this perspective, we provide a conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis. Understanding these concepts will progressively support the development of new strategies to treat human cancer.

1,850 citations


Cites background from "The emerging role of the Nrf2–Keap1..."

  • ...Specifically, NRF2 is activated following disruption of the interaction of NRF2 with its binding partner Kelch-like ECH-associated protein 1 (KEAP1)....

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  • ...Critical cysteine residues within KEAP1 can undergo oxidation, succination, and glutathionylation, thereby inhibiting theKEAP1-NRF2 interaction, leading to the proteasomal degradation of NRF2....

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  • ...Once activated, NRF2 induces the transcription of many antioxidant proteins including GPXs and TXNs as well as enzymes involved inGSHsynthesis and cysteine import through the cystine/ glutamate antiporter....

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  • ...NRF2 also regulates the serine biosynthesis pathway, generating NADPH in the mitochondria, which is critical for redox balance under hypoxic conditions (129, 130)....

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  • ...One mechanism by which cancer cells increase their antioxidant capacity is by activating the transcription factor nuclear factor (erythroidderived 2)–related factor-2 (NRF2) (127)....

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Journal ArticleDOI
TL;DR: Observations suggest Nrf2 directs metabolic reprogramming during stress, which would enable the factor to orchestrate adaptive responses to diverse forms of stress.

1,482 citations

Journal ArticleDOI
20 May 2014-eLife
TL;DR: Dixon, Patel, et al. as mentioned in this paper found that erastin is a very effective inhibitor of system xc− function and that it is over 1000 times more potent than the previously known best inhibitor, sulfasalazine.
Abstract: Sugars, fats, amino acids, and other nutrients cannot simply diffuse into the cell. Rather, they must be transported across the cell membrane by specific proteins that stretch from one side of the cell membrane to the other. One such ‘transporter’—system xc−—is of special interest. This transporter imports one molecule of cystine from outside the cell in exchange for one molecule of glutamate from inside the cell. Cystine, a variant of the amino acid cysteine, is essential for synthesizing new proteins and for preventing the accumulation of toxic species inside the cell. Not surprisingly, many cancer cells are dependent upon the transport activity of system xc− for growth and survival. Drugs that can inhibit system xc− could therefore be part of potential treatments for cancer and other diseases. Dixon, Patel, et al. have found that the compound erastin is a very effective inhibitor of system xc− function. Certain versions of erastin are over 1000 times more potent than the previously known best inhibitor of system xc−, sulfasalazine. Dixon, Patel et al. found that using erastin and sulfasalazine to inhibit system xc− in cancer cells grown in a petri dish results in an unusual type of iron-dependent cell death called ferroptosis. By inhibiting the uptake of cystine, erastin and other system xc− inhibitors interfere with the cellular machinery that folds proteins into their final, three-dimensional shape. The accumulation of these partially-folded proteins in the cell causes a specific kind of cellular stress that can be used as a readout, or biomarker, for the inhibition of system xc−. Such a biomarker will be essential for identifying cells in the body that have been exposed to agents that inhibit system xc− and that are undergoing ferroptosis. Unexpectedly, Dixon, Patel et al. also found that the FDA-approved anti-cancer drug sorafenib inhibits system xc−. Other drugs in the same class as sorafenib do not share this unusual property. Dixon, Patel, et al. synthesized variants of sorafenib and identified sites on the drug that are necessary for it to be able to interfere with system xc−. Alongside the erastin derivatives, these new molecules may help to develop new drugs that can inhibit this important transporter in a clinical setting.

1,137 citations


Cites background from "The emerging role of the Nrf2–Keap1..."

  • ...Mutations of both these genes are observed in numerous cancers (Jaramillo and Zhang, 2013), and we would predict that these changes enhance AKR1C expression and possibly render cells resistant to the induction of ferroptosis downstream of system xc− inhibition....

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  • ...Mutations of both these genes are observed in numerous cancers 684 (Jaramillo and Zhang, 2013) and we would predict that these changes enhance 685 AKR1C expression and possibly render cells resistant to the induction of 686 ferroptosis downstream of system xc inhibition....

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Journal ArticleDOI
TL;DR: It is reported that nuclear factor erythroid 2‐related factor 2 (NRF2) plays a central role in protecting hepatocellular carcinoma (HCC) cells against ferroptosis, and the status of NRF2 is a key factor that determines the therapeutic response to ferroPTosis‐targeted therapies in HCC cells.

1,066 citations


Cites background from "The emerging role of the Nrf2–Keap1..."

  • ...type and stage of the cancer.(7,8) For example, NRF2 prevents the initiation but accelerates the progression of chemical carcinogen-mediated or oncogene-mediated carcinogenesis....

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References
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Journal ArticleDOI
23 Jan 2004-Cell
TL;DR: Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.

32,946 citations

Journal ArticleDOI
TL;DR: It is demonstrated that Nrf2 is essential for the transcriptional induction of phase II enzymes and the presence of a coordinate transcriptional regulatory mechanism for phase II enzyme genes and the nrf2-deficient mice may prove to be a very useful model for the in vivo analysis of chemical carcinogenesis and resistance to anti-cancer drugs.

3,557 citations


"The emerging role of the Nrf2–Keap1..." refers background in this paper

  • ...In the nucleus, Nrf2 dimerizes with members of the masculoaponeurotic fibrosarcoma (Maf) protein family that have been shown to facilitate the binding of Nrf2 to AREs located within the regulatory regions of a wide variety of genes involved in cytoprotection and metabolism (Itoh et al. 1997; Nguyen et al. 2000; Motohashi et al. 2004; Hirotsu et al. 2012)....

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  • ...…fibrosarcoma (Maf) protein family that have been shown to facilitate the binding of Nrf2 to AREs located within the regulatory regions of a wide variety of genes involved in cytoprotection and metabolism (Itoh et al. 1997; Nguyen et al. 2000; Motohashi et al. 2004; Hirotsu et al. 2012)....

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Journal ArticleDOI
TL;DR: It is postulate that Keap1 and Nrf2 constitute a crucial cellular sensor for oxidative stress, and together mediate a key step in the signaling pathway that leads to transcriptional activation by this novel NRF2 nuclear shuttling mechanism.
Abstract: Transcription factor Nrf2 is essential for the antioxidant responsive element (ARE)-mediated induction of phase II detoxifying and oxidative stress enzyme genes. Detailed analysis of differential Nrf2 activity displayed in transfected cell lines ultimately led to the identification of a new protein, which we named Keap1, that suppresses Nrf2 transcriptional activity by specific binding to its evolutionarily conserved amino-terminal regulatory domain. The closest homolog of Keap1 is a Drosophila actin-binding protein called Kelch, implying that Keap1 might be a Nrf2 cytoplasmic effector. We then showed that electrophilic agents antagonize Keap1 inhibition of Nrf2 activity in vivo, allowing Nrf2 to traverse from the cytoplasm to the nucleus and potentiate the ARE response. We postulate that Keap1 and Nrf2 constitute a crucial cellular sensor for oxidative stress, and together mediate a key step in the signaling pathway that leads to transcriptional activation by this novel Nrf2 nuclear shuttling mechanism. The activation of Nrf2 leads in turn to the induction of phase II enzyme and antioxidative stress genes in response to electrophiles and reactive oxygen species.

3,166 citations


"The emerging role of the Nrf2–Keap1..." refers background in this paper

  • ...The Kelch/DGR domain is critical for maintaining the interaction between Nrf2 and Keap1 by interacting with the Neh2 domain of Nrf2 (Itoh et al. 1999; McMahon et al. 2004)....

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PatentDOI
13 Aug 2007-Science
TL;DR: In this paper, the authors analyzed 13,023 genes in 11 breast and 11 colorectal cancers and found that individual tumors accumulate an average of 90 mutant genes but only a subset of these contribute to the neoplastic process.
Abstract: Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of ˜90 mutant genes but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, we identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. These data define the genetic landscape of two human cancer types, provide new targets for diagnostic and therapeutic intervention and monitoring.

3,152 citations

Journal ArticleDOI
TL;DR: The development of Nrf2 knockout mice has provided key insights into the toxicological importance of this pathway, and this review highlights the key elements in this adaptive response to protection against acute and chronic cell injury provoked by environmental stresses.
Abstract: Keap1-Nrf2-ARE signaling plays a significant role in protecting cells from endogenous and exogenous stresses. The development of Nrf2 knockout mice has provided key insights into the toxicological importance of this pathway. These mice are more sensitive to the hepatic, pulmonary, ovarian, and neurotoxic consequences of acute exposures to environmental agents and drugs, inflammatory stresses, as well as chronic exposures to cigarette smoke and other carcinogens. Under quiescent conditions, the transcription factor Nrf2 interacts with the actin-anchored protein Keap1, largely localized in the cytoplasm. This quenching interaction maintains low basal expression of Nrf2-regulated genes. However, upon recognition of chemical signals imparted by oxidative and electrophilic molecules, Nrf2 is released from Keap1, escapes proteasomal degradation, translocates to the nucleus, and transactivates the expression of several dozen cytoprotective genes that enhance cell survival. This review highlights the key elements in this adaptive response to protection against acute and chronic cell injury provoked by environmental stresses.

3,066 citations


"The emerging role of the Nrf2–Keap1..." refers background in this paper

  • ...Activation of the Nrf2 defense response has been shown to protect against neurodegenerative diseases, aging, diabetes, photo-oxidative stress, cardiovascular disease, inflammation, pulmonary fibrosis, acute pulmonary injury, and cancer (for review, see Motohashi and Yamamoto 2004; Jeong et al. 2006; Zhang 2006; Kensler et al. 2007; Lau et al. 2008)....

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  • ...…to protect against neurodegenerative diseases, aging, diabetes, photo-oxidative stress, cardiovascular disease, inflammation, pulmonary fibrosis, acute pulmonary injury, and cancer (for review, see Motohashi and Yamamoto 2004; Jeong et al. 2006; Zhang 2006; Kensler et al. 2007; Lau et al. 2008)....

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