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      Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis

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          Abstract

          Cancer cells are hallmarked by high proliferation and imbalanced redox consumption and signaling. Various oncogenic pathways such as proliferation and evading cell death converge on redox-dependent signaling processes. Nrf2 is a key regulator in these redox-dependent events and operates in cytoprotection, drug metabolism and malignant progression in cancer cells. Here, we show that patients with primary malignant brain tumors (glioblastomas, WHO °IV gliomas, GBM) have a devastating outcome and overall reduced survival when Nrf2 levels are upregulated. Nrf2 overexpression or Keap1 knockdown in glioma cells accelerate proliferation and oncogenic transformation. Further, activation of the Nrf2-Keap1 signaling upregulates xCT (aka SLC7A11 or system X c ) and amplifies glutamate secretion thereby impacting on the tumor microenvironment. Moreover, both fostered Nrf2 expression and conversely Keap1 inhibition promote resistance to ferroptosis. Altogether, the Nrf2-Keap1 pathway operates as a switch for malignancy in gliomas promoting cell proliferation and resistance to cell death processes such as ferroptosis. Our data demonstrate that the Nrf2-Keap1 pathway is critical for cancer cell growth and operates on xCT. Nrf2 presents the Achilles’ heel of cancer cells and thus provides a valid therapeutic target for sensitizing cancer for chemotherapeutics.

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          Most cited references37

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          Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region.

          Hypersensitive site 2 located in the beta-globin locus control region confers high levels of expression to the genes of the beta-globin cluster. A tandem repeat of the consensus sequence for the transcription factors AP1 and NF-E2 (activating protein 1 and nuclear factor erythroid 2, respectively) is present within hypersensitive site 2 and is absolutely required for strong enhancer activity. This sequence binds, in vitro and in vivo, to ubiquitous proteins of the AP1 family and to the recently cloned erythroid-specific transcription factor NF-E2. Using the tandem repeat as a recognition site probe to screen a lambda gt11 cDNA expression library from K562 cells, we isolated several DNA binding proteins. Here, we report the characterization of one of the clones isolated. The gene, which we named Nrf2 (NF-E2-related factor 2), is encoded within a 2.2-kb transcript and predicts a 66-kDa protein with a basic leucine zipper DNA binding domain highly homologous to that of NF-E2. Although Nrf2 is expressed ubiquitously, a role of this protein in mediating enhancer activity of hypersensitive site 2 in erythroid cells cannot be excluded. In this respect, Nrf2 contains a powerful acidic activation domain that may participate in the transcriptional stimulation of beta-globin genes.
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            Guidelines for the selection of highly effective siRNA sequences for mammalian and chick RNA interference.

            In the present study, the relationship between short interfering RNA (siRNA) sequence and RNA interference (RNAi) effect was extensively analyzed using 62 targets of four exogenous and two endogenous genes and three mammalian and Drosophila cells. We present the rules that may govern siRNA sequence preference and in accordance with which highly effective siRNAs essential for systematic mammalian functional genomics can be readily designed. These rules indicate that siRNAs which simultaneously satisfy all four of the following sequence conditions are capable of inducing highly effective gene silencing in mammalian cells: (i) A/U at the 5' end of the antisense strand; (ii) G/C at the 5' end of the sense strand; (iii) at least five A/U residues in the 5' terminal one-third of the antisense strand; and (iv) the absence of any GC stretch of more than 9 nt in length. siRNAs opposite in features with respect to the first three conditions give rise to little or no gene silencing in mammalian cells. Essentially the same rules for siRNA sequence preference were found applicable to DNA-based RNAi in mammalian cells and in ovo RNAi using chick embryos. In contrast to mammalian and chick cells, little siRNA sequence preference could be detected in Drosophila in vivo RNAi.
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              Dual roles of Nrf2 in cancer.

              In response to oxidative stress, the transcription factor NF-E2-related factor 2 (Nrf2) controls the fate of cells through transcriptional upregulation of antioxidant response element (ARE)-bearing genes, including those encoding endogenous antioxidants, phase II detoxifying enzymes, and transporters. Expression of the Nrf2-dependent proteins is critical for ameliorating or eliminating toxicants/carcinogens to maintain cellular redox homeostasis. As a result, activation of the Nrf2 pathway, by naturally-occurring compounds or synthetic chemicals at sub-toxic doses, confers protection against subsequent toxic/carcinogenic exposure. Thus, the use of dietary compounds or synthetic chemicals to boost the Nrf2-dependent adaptive response to counteract environmental insults has emerged to be a promising strategy for cancer prevention. Interestingly, recent emerging data has revealed the "dark" side of Nrf2. Nrf2 and its downstream genes are overexpressed in many cancer cell lines and human cancer tissues, giving cancer cells an advantage for survival and growth. Furthermore, Nrf2 is upregulated in resistant cancer cells and is thought to be responsible for acquired chemoresistance. Therefore, it may be necessary to inhibit the Nrf2 pathway during chemotherapy. This review is primarily focused on the role of Nrf2 in cancer, with emphasis on the recent findings indicating the cancer promoting function of Nrf2 and its role in acquired chemoresistance.
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                Author and article information

                Journal
                Oncogenesis
                Oncogenesis
                Oncogenesis
                Nature Publishing Group
                2157-9024
                August 2017
                14 August 2017
                1 August 2017
                : 6
                : 8
                : e371
                Affiliations
                [1 ]Translational Cell Biology and Neurooncology Laboratory at the Department of Neurosurgery, University Medical School Hospital Universitätsklinikum Erlangen (UKER), Friedrich-Alexander University of Erlangen–Nürnberg (FAU) , Erlangen, Germany
                [2 ]Laboratory of Exercise and Health, Institute of Movement Sciences, Department of Health Sciences and Technology, (D-HEST) , ETH Zürich, Schwerzenbach, Switzerland
                [3 ]Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health , Munich, Germany
                [4 ]Department of Otolaryngology–Head and Neck Surgery, Chinese PLA General Hospital , Beijing, China
                [5 ]Institute of Anatomy and Cell Biology, Universitätsklinikum RWTH Aachen , Aachen, Germany
                [6 ]Department of Pediatrics and Adolescent Medicine, University Medical School Hospital Erlangen (UKER), Friedrich-Alexander University of Erlangen–Nürnberg (FAU) , Erlangen, Germany
                [7 ]BiMECON , Berlin, Germany
                Author notes
                [* ]BiMECON and Department of Neurosurgery, University of Erlangen–Nürnberg (FAU) , Schwabachanlage 6, Erlangen 91054, Germany. E-mail: savaskan@ 123456gmx.net or nic.savaskan@ 123456gmail.com
                Author information
                http://orcid.org/0000-0003-1348-094X
                Article
                oncsis201765
                10.1038/oncsis.2017.65
                5608917
                28805788
                cfa73164-de25-4fb2-ac83-233b7ce81904
                Copyright © 2017 The Author(s)

                Oncogenesis is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 28 December 2016
                : 05 June 2017
                : 27 June 2017
                Categories
                Original Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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