title: A dangerous liaison: Leptin and sPLA2-IIA join forces to induce proliferation and migration of astrocytoma cells.
abstract: Glioblastoma, the most aggressive type of primary brain tumour, shows worse prognosis linked to diabetes or obesity persistence. These pathologies are chronic inflammatory conditions characterized by altered profiles of inflammatory mediators, including leptin and secreted phospholipase A2-IIA (sPLA2-IIA). Both proteins, in turn, display diverse pro-cancer properties in different cell types, including astrocytes. Herein, to understand the underlying relationship between obesity and brain tumors, we investigated the effect of leptin, alone or in combination with sPLA2-IIA on astrocytoma cell functions. sPLA2-IIA induced up-regulation of leptin receptors in 1321N1 human astrocytoma cells. Leptin, as well as sPLA2-IIA, increased growth and migration in these cells, through activation/phosphorylation of key proteins of survival cascades. Leptin, at concentrations with minimal or no activating effects on astrocytoma cells, enhanced growth and migration promoted by low doses of sPLA2-IIA. sPLA2-IIA alone induced a transient phosphorylation pattern in the Src/ERK/Akt/mTOR/p70S6K/rS6 pathway through EGFR transactivation, and co-addition of leptin resulted in a sustained phosphorylation of these signaling regulators. Mechanistically, EGFR transactivation and tyrosine- and serine/threonine-protein phosphatases revealed a key role in this leptin-sPLA2-IIA cross-talk. This cooperative partnership between both proteins was also found in primary astrocytes. These findings thus indicate that the adipokine leptin, by increasing the susceptibility of cells to inflammatory mediators, could contribute to worsen the prognosis of tumoral and neurodegenerative processes, being a potential mediator of some obesity-related medical complications.
authors.affiliation: Instituto de Biología y Genética Molecular (IBGM), CSIC-UVa, Valladolid, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: Martín
authors.affiliation: Instituto de Biología y Genética Molecular (IBGM), CSIC-UVa, Valladolid, Spain.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cordova
authors.affiliation: Instituto de Biología y Genética Molecular (IBGM), CSIC-UVa, Valladolid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Gutiérrez
authors.affiliation: Instituto de Biología y Genética Molecular (IBGM), CSIC-UVa, Valladolid, Spain.
authors.forename: Marita
authors.initials: M
authors.lastname: Hernández
authors.affiliation: Instituto de Biología y Genética Molecular (IBGM), CSIC-UVa, Valladolid, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: Nieto
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020738:Leptin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D051379:Mice; D054497:Phospholipases A2, Secretory / Q000096:biosynthesis* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin / Q000096:biosynthesis / Q000235:genetics; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D020738:Leptin; D054411:Receptors, Leptin; C546842:MTOR protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D016392:Proto-Oncogene Proteins pp60(c-src); D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D054497:Phospholipases A2, Secretory