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      OncoTargets and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the pathological basis of cancers, potential targets for therapy and treatment protocols to improve the management of cancer patients. Publishing high-quality, original research on molecular aspects of cancer, including the molecular diagnosis, since 2008. Sign up for email alerts here. 50,877 Monthly downloads/views I 4.345 Impact Factor I 7.0 CiteScore I 0.81 Source Normalized Impact per Paper (SNIP) I 0.811 Scimago Journal & Country Rank (SJR)

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      The NRF2/KEAP1 Pathway Modulates Nasopharyngeal Carcinoma Cell Radiosensitivity via ROS Elimination

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          Abstract

          Purpose

          Radioresistance is a vital obstacle for the prognosis of human nasopharyngeal carcinoma (NPC), but the underlying mechanism is still unknown. Here, we explored the role of the NRF2/KEAP1 pathway in radioresistance of NPC cell lines.

          Materials and Methods

          We selected NPC cell lines CNE-1 and CNE-2, treated them with ionization, and subsequently determined the levels of NRF2, KEAP1, antioxidant enzymes, and ROS. We then evaluated the effect of NRF2 or KEAP1 inhibition on cell proliferation, colony formation, and radiosensitivity in CNE2 cells.

          Results

          We discovered that the NRF2/KEAP1 signaling pathway can be activated by radiotherapy in NPC cells, while NRF2 knockdown enhances the sensitivity of CNE-2 cells to radiation treatment. In contrast, the silencing of KEAP1 inhibits the sensitivity of CNE-2 cells to radiation treatment.

          Conclusion

          Our results suggest that NRF2/KEAP1 signaling may serve as an essential regulator of the radioresistance of NPC and may be applied as a novel therapeutic approach for the sensitization of NPC to radiation.

          Most cited references17

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          Antioxidants Maintain Cellular Redox Homeostasis by Elimination of Reactive Oxygen Species.

          Reactive oxygen species (ROS) are produced by living cells as normal cellular metabolic byproduct. Under excessive stress conditions, cells will produce numerous ROS, and the living organisms eventually evolve series of response mechanisms to adapt to the ROS exposure as well as utilize it as the signaling molecules. ROS molecules would trigger oxidative stress in a feedback mechanism involving many biological processes, such as apoptosis, necrosis and autophagy. Growing evidences have suggested that ROS play a critical role as the signaling molecules throughout the entire cell death pathway. Overwhelming production of ROS can destroy organelles structure and bio-molecules, which lead to inflammatory response that is a known underpinning mechanism for the development of diabetes and cancer. Cytochrome P450 enzymes (CYP) are regarded as the markers of oxidative stress, can transform toxic metabolites into ROS, such as superoxide anion, hydrogen peroxide and hydroxyl radical which might cause injury of cells. Accordingly, cells have evolved a balanced system to neutralize the extra ROS, namely antioxidant systems that consist of enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidases (GPxs), thioredoxin (Trx) as well as the non-enzymatic antioxidants which collectively reduce oxidative state. Herein, we review the recent novel findings of cellular processes induced by ROS, and summarize the roles of cellular endogenous antioxidant systems as well as natural anti-oxidative compounds in several human diseases caused by ROS in order to illustrate the vital role of antioxidants in prevention against oxidative stress.
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            Induction of reactive oxygen species: an emerging approach for cancer therapy.

            Reactive oxygen species (ROS), a group of ions and molecules, include hydroxyl radicals (·OH), alkoxyl radicals, superoxide anion (O2·-), singlet oxygen (1O2) and hydrogen peroxide (H2O2). Hydroxyl radicals and alkoxyl radicals are extremely and highly reactive species respectively. Endogenous ROS are mainly formed in mitochondrial respiratory chain. Low levels of ROS play important roles in regulating biological functions in mammalian cells. However, excess production of ROS can induce cell death by oxidative damaging effects to intracellular biomacromolecules. Cancer cell death types induced by ROS include apoptotic, autophagic, ferroptotic and necrotic cell death. Since abnormal metabolism in cancer cells, they have higher ROS content compared to normal cells. The higher endogenous ROS levels in cancer cells endow them more susceptible to the ROS-induction treatment. Indeed, some anticancer drugs currently used in clinic, such as molecular targeted drugs and chemotherapeutic agents, effectively kill cancer cells by inducing ROS generation. In addition, photodynamic therapy (PDT) is mainly based on induction of ROS burst to kill cancer cells. The mechanism of cell death induced by radiotherapy using ionizing radiation also refers to ROS production. Moreover, ROS play an important role in tumor immune therapy. Altogether, combining above traditional treatments with ROS-induced agents will be considered as a promising strategy in cancer therapy. In this review, we focus on our current understanding of the anticancer effects of ROS.
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              Nrf2 in cancers: A double‐edged sword

              Abstract The Nrf2/Keap1 pathway is an important signaling cascade responsible for the resistance of oxidative damage induced by exogenous chemicals. It maintains the redox homeostasis, exerts anti‐inflammation and anticancer activity by regulating its multiple downstream cytoprotective genes, thereby plays a vital role in cell survival. Interestingly, in recent years, accumulating evidence suggests that Nrf2 has a contradictory role in cancers. Aberrant activation of Nrf2 is associated with poor prognosis. The constitutive activation of Nrf2 in various cancers induces pro‐survival genes and promotes cancer cell proliferation by metabolic reprogramming, repression of cancer cell apoptosis, and enhancement of self‐renewal capacity of cancer stem cells. More importantly, Nrf2 is proved to contribute to the chemoresistance and radioresistance of cancer cells as well as inflammation‐induced carcinogenesis. A number of Nrf2 inhibitors discovered for cancer treatment were reviewed in this report. These provide a new strategy that targeting Nrf2 could be a promising therapeutic approach against cancer. This review aims to summarize the dual effects of Nrf2 in cancer, revealing its function both in cancer prevention and inhibition, to further discover novel anticancer treatment.
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                Author and article information

                Journal
                Onco Targets Ther
                Onco Targets Ther
                ott
                ott
                OncoTargets and therapy
                Dove
                1178-6930
                11 September 2020
                2020
                : 13
                : 9113-9122
                Affiliations
                [1 ]Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Ear Institute, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases , Shanghai, People’s Republic of China
                [2 ]Department of Radiation Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine , Shanghai, People’s Republic of China
                [3 ]Department of Otolaryngology, Zhangjiagang First People’s Hospital, Affiliated Hospital of Soochow University , Suzhou, Jiangsu Province, People’s Republic of China
                Author notes
                Correspondence: Dong Li; Zhentao Wang Email lidong@shsmu.edu.cn; 13916548333@163.com
                [*]

                These authors contributed equally to this work

                Author information
                http://orcid.org/0000-0002-2640-9539
                Article
                260169
                10.2147/OTT.S260169
                7494231
                32982300
                aae533e3-af6b-4e2d-8a9f-1a8eb025482d
                © 2020 Zhou et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 04 May 2020
                : 08 August 2020
                Page count
                Figures: 5, Tables: 1, References: 25, Pages: 10
                Funding
                Funded by: Fundamental Research Program Funding of Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine;
                Funded by: National Natural Science Foundation of China, open-funder-registry 10.13039/501100001809;
                Funded by: Program for Professor of Special Appointment;
                This study was supported by the Fundamental Research Program Funding of Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine under Grant JYZ005 (Jieyu Zhou), National Natural Science Foundation of China under Grant 81970094 (Ding Li) and The Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (TP2015022, Dong Li).
                Categories
                Original Research

                Oncology & Radiotherapy
                nasopharyngeal carcinoma,nrf2,keap1,radiosensitivity
                Oncology & Radiotherapy
                nasopharyngeal carcinoma, nrf2, keap1, radiosensitivity

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