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      BPIFB1 (LPLUNC1) inhibits radioresistance in nasopharyngeal carcinoma by inhibiting VTN expression

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          Abstract

          Bactericidal/permeability-increasing-fold-containing family B member 1 (BPIFB1, previously named LPLUNC1) is highly expressed in the nasopharynx and significantly downregulated in nasopharyngeal carcinoma (NPC). Low expression is also associated with poor prognosis in patients with NPC. Radiotherapy is a routine treatment for NPC; however, radioresistance is a major cause of treatment failure. Thus, we aimed to investigate the role of BPIFB1 in the radioresponse of NPC. Colony formation and cell survival results showed that BPIFB1 sensitized NPC cells to ionizing radiation. VTN, a previously identified BPIFB1-binding protein, was shown to induce cell proliferation and survival, G2/M phase arrest, DNA repair, activation of the ATM-Chk2 and ATR-Chk1 pathways, and anti-apoptotic effects after exposure to radiation, facilitating NPC cell radioresistance. However, BPIFB1 inhibited this VTN-mediated radioresistance, ultimately improving NPC radiosensitivity. In conclusion, this study is the first to demonstrate the functions of BPIFB1 and VTN in the NPC radioresponse. Our findings indicated that promoting BPIFB1 expression and targeting VTN might represent new therapeutic strategies for NPC.

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          Most cited references36

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          Old, new and emerging functions of caspases.

          Caspases are proteases with a well-defined role in apoptosis. However, increasing evidence indicates multiple functions of caspases outside apoptosis. Caspase-1 and caspase-11 have roles in inflammation and mediating inflammatory cell death by pyroptosis. Similarly, caspase-8 has dual role in cell death, mediating both receptor-mediated apoptosis and in its absence, necroptosis. Caspase-8 also functions in maintenance and homeostasis of the adult T-cell population. Caspase-3 has important roles in tissue differentiation, regeneration and neural development in ways that are distinct and do not involve any apoptotic activity. Several other caspases have demonstrated anti-tumor roles. Notable among them are caspase-2, -8 and -14. However, increased caspase-2 and -8 expression in certain types of tumor has also been linked to promoting tumorigenesis. Increased levels of caspase-3 in tumor cells causes apoptosis and secretion of paracrine factors that promotes compensatory proliferation in surrounding normal tissues, tumor cell repopulation and presents a barrier for effective therapeutic strategies. Besides this caspase-2 has emerged as a unique caspase with potential roles in maintaining genomic stability, metabolism, autophagy and aging. The present review focuses on some of these less studied and emerging functions of mammalian caspases.
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            The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer.

            DNA damage is a key factor both in the evolution and treatment of cancer. Genomic instability is a common feature of cancer cells, fuelling accumulation of oncogenic mutations, while radiation and diverse genotoxic agents remain important, if imperfect, therapeutic modalities. Cellular responses to DNA damage are coordinated primarily by two distinct kinase signaling cascades, the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. Historically, these pathways were thought to act in parallel with overlapping functions; however, more recently it has become apparent that their relationship is more complex. In response to DSBs, ATM is required both for ATR-Chk1 activation and to initiate DNA repair via homologous recombination (HRR) by promoting formation of single-stranded DNA at sites of damage through nucleolytic resection. Interestingly, cells and organisms survive with mutations in ATM or other components required for HRR, such as BRCA1 and BRCA2, but at the cost of genomic instability and cancer predisposition. By contrast, the ATR-Chk1 pathway is the principal direct effector of the DNA damage and replication checkpoints and, as such, is essential for the survival of many, although not all, cell types. Remarkably, deficiency for HRR in BRCA1- and BRCA2-deficient tumors confers sensitivity to cisplatin and inhibitors of poly(ADP-ribose) polymerase (PARP), an enzyme required for repair of endogenous DNA damage. In addition, suppressing DNA damage and replication checkpoint responses by inhibiting Chk1 can enhance tumor cell killing by diverse genotoxic agents. Here, we review current understanding of the organization and functions of the ATM-Chk2 and ATR-Chk1 pathways and the prospects for targeting DNA damage signaling processes for therapeutic purposes. Copyright © 2010 Elsevier Inc. All rights reserved.
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              Management of Nasopharyngeal Carcinoma: Current Practice and Future Perspective.

              Nasopharyngeal carcinoma of the undifferentiated subtype is endemic to southern China, and patient prognosis has improved significantly over the past three decades because of advances in disease management, diagnostic imaging, radiotherapy technology, and broader application of systemic therapy. Despite the excellent local control with modern radiotherapy, distant failure remains a key challenge. Advances in molecular technology have helped to decipher the molecular pathogenesis of nasopharyngeal carcinoma as well as its etiologic association with the Epstein-Barr virus. This in turn has led to the discovery of novel biomarkers and drug targets, rendering this cancer site a current focus for new drug development. This article reviews and appraises the key literature on the current management of nasopharyngeal carcinoma and future directions in clinical research.
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                Author and article information

                Contributors
                xiongwei@csu.edu.cn
                zengzhaoyang@csu.edu.cn
                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                2041-4889
                22 March 2018
                22 March 2018
                April 2018
                : 9
                : 4
                : 432
                Affiliations
                [1 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, , Central South University, ; Changsha, Hunan China
                [2 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, , Central South University, ; Changsha, Hunan China
                [3 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, , Central South University, ; Changsha, Hunan China
                [4 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, , Central South University, ; Changsha, Hunan China
                [5 ]ISNI 0000 0001 0675 4725, GRID grid.239578.2, Department of Cancer Biology, , Lerner Research Institute, Cleveland Clinic, ; Cleveland, OH USA
                Article
                409
                10.1038/s41419-018-0409-0
                5864881
                29568064
                53289c17-e065-4231-b8c1-7d8d1e49eaa3
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 9 October 2017
                : 15 February 2018
                : 16 February 2018
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                © The Author(s) 2018

                Cell biology
                Cell biology

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