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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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      Identification of Pannexin 2 as a Novel Marker Correlating with Ferroptosis and Malignant Phenotypes of Prostate Cancer Cells

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          Abstract

          Purpose

          Prostate cancer (PCa) is a widespread urinary neoplasm and one of the most prevalent and second most frequent malignancies diagnosed in males worldwide. This study aimed to identify a candidate marker and explore its molecular mechanism in PCa.

          Methods

          Gene expression datasets, GSE55945 (n=21) and GSE46602 (n=50), were downloaded from the Gene Expression Omnibus database. Bioinformatic approaches were applied to identify potential markers. Effects of the candidate marker on proliferation, migration, invasion, and ferroptosis (ferrous iron and malondialdehyde (MDA)) in PCa cells and its mechanism were assessed after performing cell transfection.

          Results

          A total of 1435 common differentially expressed genes were identified in GSE55945 and GSE46602. Five key gene modules were listed based on a protein–protein interaction network, containing five hub genes. Pannexin 2 ( PANX2), a candidate marker was identified, and findings revealed substantial upregulation of its expression levels in PCa cell lines. Blocking expression of PANX2 resulted in suppression of proliferation, migration, and invasion in PCa cells, while increasing ferrous iron and MDA levels. However, these effects were rescued by Nrf2 activator, oltipraz. The Nrf2 signaling pathway was consequently applied to determine underlying mechanism of PANX2 in PCa cells. We established that silencing PANX2 remarkably reduced protein expression levels in members of Nrf2 signaling pathway ( Nrf2, HO-1, and FTH1).

          Conclusion

          Our study demonstrated that PANX2 is implicated in the pathogenesis of PCa, which regulates malignant phenotypes and ferroptosis through Nrf2 signaling pathway, and maybe a potential therapeutic target for PCa.

          Most cited references19

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          Gene Ontology: tool for the unification of biology

          Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
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            Detecting overlapping protein complexes in protein-protein interaction networks.

            We introduce clustering with overlapping neighborhood expansion (ClusterONE), a method for detecting potentially overlapping protein complexes from protein-protein interaction data. ClusterONE-derived complexes for several yeast data sets showed better correspondence with reference complexes in the Munich Information Center for Protein Sequence (MIPS) catalog and complexes derived from the Saccharomyces Genome Database (SGD) than the results of seven popular methods. The results also showed a high extent of functional homogeneity.
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              Lipid Peroxidation-Dependent Cell Death Regulated by GPx4 and Ferroptosis.

              Glutathione peroxidase 4 (Phospholipid hydroperoxide glutathione peroxidase, PHGPx) can directly reduce phospholipid hydroperoxide. Depletion of GPx4 induces lipid peroxidation-dependent cell death in embryo, testis, brain, liver, heart, and photoreceptor cells of mice. Administration of vitamin E in tissue specific GPx4 KO mice restored tissue damage in testis, liver, and heart. These results indicate that suppression of phospholipid peroxidation is essential for cell survival in normal tissues in mice. Ferroptosis is an iron-dependent non-apoptotic cell death that can elicited by pharmacological inhibiting the cystine/glutamate antiporter, system Xc- (type I) or directly binding and loss of activity of GPx4 (Type II) in cancer cells with high level RAS-RAF-MEK pathway activity or p53 expression, but not in normal cells. Ferroptosis by Erastin (Type I) and RSL3 (RAS-selective lethal 3, Type II) treatment was suppressed by an iron chelator, vitamin E and Ferrostatin-1, antioxidant compound. GPx4 can regulate ferroptosis by suppression of phospholipid peroxidation in erastin and RSL3-induced ferroptosis. Recent works have identified several regulatory factors of erastin and RSL3-induced ferroptosis. In our established GPx4-deficient MEF cells, depletion of GPx4 induce iron and 15LOX-independent lipid peroxidation at 26 h and caspase-independent cell death at 72 h, whereas erastin and RSL3 treatment resulted in iron-dependent ferroptosis by 12 h. These results indicated the possibility that the mechanism of GPx4-depleted cell death might be different from that of ferroptosis induced by erastin and RSL3.
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                Author and article information

                Journal
                Onco Targets Ther
                Onco Targets Ther
                OTT
                ott
                OncoTargets and therapy
                Dove
                1178-6930
                19 May 2020
                2020
                : 13
                : 4411-4421
                Affiliations
                [1 ]Department of Urology Surgery, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital , Chengdu, Sichuan, People’s Republic of China
                [2 ]Department of Urology Surgery, The First Affiliated Hospital of Chongqing Medical University , Chongqing, People’s Republic of China
                [3 ]Department of Neurosurgery, West China Hospital, Sichuan University , Chengdu, People’s Republic of China
                [4 ]Department of Dermatology, Chongqing Traditional Chinese Medicine Hospital , Chongqing, People’s Republic of China
                [5 ]Department of Critical Care Medicine, Children’s Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders , Chongqing, People’s Republic of China
                Author notes
                Correspondence: Jichun Shao Department of Urology Surgery, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation , 416 Hospital, 4# Second Ring Road, North Fourth Section, Chengdu, Sichuan610057, People’s Republic of China Email shaoji93@163.com
                Qi Pan Department of Dermatology, Chongqing Traditional Chinese Medicine Hospital , 40# Daomenkou, Yuzhong District, Chongqing400011, People’s Republic of China Email qi_pan@vip.sina.com
                [*]

                These authors contributed equally to this work

                Article
                249752
                10.2147/OTT.S249752
                7245471
                32547072
                aa532dcd-4d6a-488c-8097-d3ba054ee2d3
                © 2020 Liao 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
                : 14 February 2020
                : 26 April 2020
                Page count
                Figures: 6, Tables: 1, References: 27, Pages: 11
                Categories
                Original Research

                Oncology & Radiotherapy
                prostate cancer,ferroptosis,panx2 and nrf2 signaling pathways
                Oncology & Radiotherapy
                prostate cancer, ferroptosis, panx2 and nrf2 signaling pathways

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