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Título: | Secreted phospholipase A2-IIA modulates key regulators of proliferation on astrocytoma cells |
Autor: | Martín, Rubén CSIC ORCID; Hernández, Marita CSIC ORCID CVN ; Ibeas, Elvira CSIC; Fuentes, Lucía CSIC; Salicio, Veronica; Arnés, Mercedes CSIC; Nieto, María Luisa CSIC ORCID | Fecha de publicación: | 2009 | Editor: | Wiley-Blackwell | Citación: | Journal of Neurochemistry 111(4): 988-999 (2009) | Resumen: | Human group IIA secreted phospholipase A2 (sPLA2-IIA) has been characterized in numerous inflammatory and neoplastic conditions. sPLA2-IIA can either promote or inhibit cell growth depending on the cellular type and the specific injury. We have previously demonstrated that exogenous sPLA2-IIA, by engagement to a membrane structure, induces proliferation and activation of mitogen-activated protein kinases cascade in human astrocytoma cells. In this study, we used human astrocytoma 1321N1 cells to investigate the key molecules mediating sPLA2-IIA-induced cell proliferation. We found that sPLA2-IIA promoted reactive oxygen species (ROS) accumulation, which was abrogated in the presence of allopurinol and DPI, but not by rotenone, discarding mitochondria as a ROS source. In addition, sPLA2-IIA triggered Ras and Raf-1 activation, with kinetics that paralleled ERK phosphorylation, and co-immunoprecipitation assays indicated an association between Ras, Raf-1 and ERK. Additionally, Akt, p70 ribosomal protein S6 kinase, and S6 ribosomal protein were also phosphorylated upon sPLA2-IIA treatment, effect that was abrogated by N-acetylcysteine or LY294002 treatment indicating that ROS and phosphatidylinositol 3 kinase are upstream signaling regulators. As the inhibitors N-acetylcysteine, PD98059, LY294002 or rapamycin blocked sPLA 2-IIA-induced proliferation without activation of the apoptotic program, we suggest that inhibition of these intracellular signal transduction elements may represent a mechanism of growth arrest. Our results reveal new potential targets for therapeutic intervention in neuroinflammatory disorders and brain cancer in particular. © 2009 International Society for Neurochemistry. | URI: | http://hdl.handle.net/10261/72762 | DOI: | 10.1111/j.1471-4159.2009.06377.x | Identificadores: | doi: 10.1111/j.1471-4159.2009.06377.x issn: 0022-3042 e-issn: 1471-4159 |
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