A dangerous liaison: Leptin and sPLA2-IIA join forces to induce proliferation and migration of astrocytoma cells

• Published in: PloS one Vol. 12; no. 3; p. e0170675
• Main Authors: Martín, Rubén, Cordova, Claudia, Gutiérrez, Beatriz, Hernández, Marita, Nieto, María L
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-03-2017; Public Library of Science (PLoS)
• Subjects: AKT protein; Analysis; Animals; Astrocytes; Astrocytoma; Astrocytoma - genetics; Astrocytoma - metabolism; Astrocytoma - pathology; Astrocytomas; Biology and Life Sciences; Brain; Brain cancer; Brain tumors; Cancer; Cascades; Cell Line, Tumor; Cell migration; Cell Movement; Cell Proliferation; Cell survival; Complications; Crosstalk; Diabetes mellitus; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glioblastoma; Health aspects; Humans; Inflammation; Kinases; Leptin; Leptin - genetics; Leptin - metabolism; Leptin - pharmacology; Leptin receptors; MAP Kinase Signaling System; Medicine and Health Sciences; Mice; Obesity; Phospholipase; Phospholipase A2; Phospholipases A2, Secretory - biosynthesis; Phospholipases A2, Secretory - genetics; Phosphorylation; Prognosis; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins pp60(c-src) - genetics; Proto-Oncogene Proteins pp60(c-src) - metabolism; Receptors; Receptors, Leptin - biosynthesis; Receptors, Leptin - genetics; Regulators; Research and Analysis Methods; Ribosomal Protein S6 Kinases, 70-kDa - genetics; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Rodents; Serine; Signaling; Threonine; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Transcriptional Activation; Tyrosine
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0170675

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.