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      FGF1 protects neuroblastoma SH-SY5Y cells from p53-dependent apoptosis through an intracrine pathway regulated by FGF1 phosphorylation

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          Abstract

          Neuroblastoma, a sympathetic nervous system tumor, accounts for 15% of cancer deaths in children. In contrast to most human tumors, p53 is rarely mutated in human primary neuroblastoma, suggesting impaired p53 activation in neuroblastoma. Various studies have shown correlations between fgf1 expression levels and both prognosis severity and tumor chemoresistance. As we previously showed that fibroblast growth factor 1 (FGF1) inhibited p53-dependent apoptosis in neuron-like PC12 cells, we initiated the study of the interaction between the FGF1 and p53 pathways in neuroblastoma. We focused on the activity of either extracellular FGF1 by adding recombinant rFGF1 in media, or of intracellular FGF1 by overexpression in human SH-SY5Y and mouse N2a neuroblastoma cell lines. In both cell lines, the genotoxic drug etoposide induced a classical mitochondrial p53-dependent apoptosis. FGF1 was able to inhibit p53-dependent apoptosis upstream of mitochondrial events in SH-SY5Y cells by both extracellular and intracellular pathways. Both rFGF1 addition and etoposide treatment increased fgf1 expression in SH-SY5Y cells. Conversely, rFGF1 or overexpressed FGF1 had no effect on p53-dependent apoptosis and fgf1 expression in neuroblastoma N2a cells. Using different FGF1 mutants (that is, FGF1 K132E, FGF1 S130A and FGF1 S130D), we further showed that the C-terminal domain and phosphorylation of FGF1 regulate its intracrine anti-apoptotic activity in neuroblastoma SH-SY5Y cells. This study provides the first evidence for a role of an intracrine growth factor pathway on p53-dependent apoptosis in neuroblastoma, and could lead to the identification of key regulators involved in neuroblastoma tumor progression and chemoresistance.

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          Most cited references63

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          The Fibroblast Growth Factor signaling pathway

          The signaling component of the mammalian Fibroblast Growth Factor (FGF) family is comprised of eighteen secreted proteins that interact with four signaling tyrosine kinase FGF receptors (FGFRs). Interaction of FGF ligands with their signaling receptors is regulated by protein or proteoglycan cofactors and by extracellular binding proteins. Activated FGFRs phosphorylate specific tyrosine residues that mediate interaction with cytosolic adaptor proteins and the RAS-MAPK, PI3K-AKT, PLCγ, and STAT intracellular signaling pathways. Four structurally related intracellular non-signaling FGFs interact with and regulate the family of voltage gated sodium channels. Members of the FGF family function in the earliest stages of embryonic development and during organogenesis to maintain progenitor cells and mediate their growth, differentiation, survival, and patterning. FGFs also have roles in adult tissues where they mediate metabolic functions, tissue repair, and regeneration, often by reactivating developmental signaling pathways. Consistent with the presence of FGFs in almost all tissues and organs, aberrant activity of the pathway is associated with developmental defects that disrupt organogenesis, impair the response to injury, and result in metabolic disorders, and cancer. © 2015 Wiley Periodicals, Inc.
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            Neuroblastoma: developmental biology, cancer genomics and immunotherapy.

            Neuroblastoma is a solid tumour that arises from the developing sympathetic nervous system. Over the past decade, our understanding of this disease has advanced tremendously. The future challenge is to apply the knowledge gained to developing risk-based therapies and, ultimately, improving outcome. In this Review we discuss the key discoveries in the developmental biology, molecular genetics and immunology of neuroblastoma, as well as new translational tools for bringing these promising scientific advances into the clinic.
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              Coordinate morphological and biochemical interconversion of human neuroblastoma cells.

              This study was undertaken to determine whether the two type of cells (one neuroblast-like and the other epithelial in appearance) of the human neuroblastoma line SK-N-SH in culture undergo morphological interconversion, whether conversion is bidirectional, and whether there are coordinate neurochemical changes. Phenotypic analysis of serially isolated neuroblast clones (SH-SY, SH-SY5, SH-SY5Y) revealed conversion to epithelial-like cells. Conversely, conversion also was promoted from an epithelial-like clone (SH-EP) to neuroblastic subclones. Cell origin could be verified because of a marker chromosome specific to SH-EP. Only neuroblastic subclones of SH-EP contained activities for tyrosine hydroxylase and dopamine-beta-hydroxylase, enzymes unique to catecholamine neurons; epithelial-like cells lacked activities for these enzymes. These findings indicate a coordinate morphological and biochemical interconversion of neuroblastoma SK-N-SH cells and reveal a plasticity in phenotypic expression in malignant neuronal cells.
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                Author and article information

                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group
                2041-4889
                August 2017
                31 August 2017
                1 August 2017
                : 8
                : 8
                : e3023
                Affiliations
                [1 ]Laboratoire de Génétique et Biologie Cellulaire, EA4589, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Paris-Saclay, École Pratique des Hautes Etudes (EPHE), PSL Research University , 2 Avenue de la Source de la Bièvre, Montigny-Le-Bretonneux 78180, France
                Author notes
                [* ]Laboratoire de Génétique et Biologie Cellulaire, EA4589 UVSQ, EPHE PSL Research University , 2 Avenue de la Source de la Bièvre, Montigny-Le-Bretonneux 78180, France. Tel: +33 17 042 9453; Fax: +0033 17 042 9403; E-mail: flore.renaud@ 123456uvsq.fr
                Article
                cddis2017404
                10.1038/cddis.2017.404
                5596585
                29048426
                fff795d2-e4fa-473f-a4c9-db0ef8226c44
                Copyright © 2017 The Author(s)

                Cell Death and Disease 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
                : 29 December 2016
                : 11 July 2017
                : 12 July 2017
                Categories
                Original Article

                Cell biology
                Cell biology

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