Pleiotrophin-induced endothelial cell migration is regulated by xanthine oxidase-mediated generation of reactive oxygen species
Autor: | Nelly Kieffer, Evangelia Papadimitriou, Maria Hatziapostolou, Margarita Lamprou, Sotiria Tsirmoula |
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Jazyk: | angličtina |
Rok vydání: | 2015 |
Předmět: |
Male
Xanthine Oxidase Alpha-v beta-3 medicine.medical_treatment CHO Cells Biology Pleiotrophin Biochemistry CSK Tyrosine-Protein Kinase chemistry.chemical_compound Phosphatidylinositol 3-Kinases Cricetulus Cell Movement Cell Line Tumor medicine Human Umbilical Vein Endothelial Cells Animals Humans Kinase activity Xanthine oxidase Inflammation NADPH oxidase Receptor-Like Protein Tyrosine Phosphatases Class 5 Growth factor Endothelial Cells Prostatic Neoplasms Cell migration Cell Biology Integrin alphaVbeta3 Molecular biology Recombinant Proteins Cell biology Endothelial stem cell src-Family Kinases chemistry biology.protein Cytokines RNA Interference Cardiology and Cardiovascular Medicine Carrier Proteins Reactive Oxygen Species |
ISSN: | 0026-2862 |
Popis: | Pleiotrophin (PTN) is a heparin-binding growth factor that induces cell migration through binding to its receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) and integrin alpha v beta 3 (ανβ3). In the present work, we studied the effect of PTN on the generation of reactive oxygen species (ROS) in human endothelial cells and the involvement of ROS in PTN-induced cell migration. Exogenous PTN significantly increased ROS levels in a concentration and time-dependent manner in both human endothelial and prostate cancer cells, while knockdown of endogenous PTN expression in prostate cancer cells significantly down-regulated ROS production. Suppression of RPTPβ/ζ through genetic and pharmacological approaches, or inhibition of c-src kinase activity abolished PTN-induced ROS generation. A synthetic peptide that blocks PTN–ανβ3 interaction abolished PTN-induced ROS generation, suggesting that ανβ3 is also involved. The latter was confirmed in CHO cells that do not express β3 or over-express wild-type β3 or mutant β3Y773F/Y785F. PTN increased ROS generation in cells expressing wild-type β3 but not in cells not expressing or expressing mutant β3. Phosphoinositide 3-kinase (PI3K) or Erk1/2 inhibition suppressed PTN-induced ROS production, suggesting that ROS production lays down-stream of PI3K or Erk1/2 activation by PTN. Finally, ROS scavenging and xanthine oxidase inhibition completely abolished both PTN-induced ROS generation and cell migration, while NADPH oxidase inhibition had no effect. Collectively, these data suggest that xanthine oxidase-mediated ROS production is required for PTN-induced cell migration through the cell membrane functional complex of ανβ3 and RPTPβ/ζ and activation of c-src, PI3K and ERK1/2 kinases. |
Databáze: | OpenAIRE |
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