Pleiotrophin-induced endothelial cell migration is regulated by xanthine oxidase-mediated generation of reactive oxygen species

Tsirmoula, S, Lamprou, M, Hatziapostolou, M ORCID: https://orcid.org/0000-0003-2493-7028, Kieffer, N and Papadimitriou, E, 2015. Pleiotrophin-induced endothelial cell migration is regulated by xanthine oxidase-mediated generation of reactive oxygen species. Microvascular Research, 98, pp. 74-81. ISSN 0026-2862

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Abstract

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.

Item Type:	Journal article
Publication Title:	Microvascular Research
Creators:	Tsirmoula, S., Lamprou, M., Hatziapostolou, M., Kieffer, N. and Papadimitriou, E.
Publisher:	Elsevier
Date:	March 2015
Volume:	98
ISSN:	0026-2862
Identifiers:	Number Type 10.1016/j.mvr.2015.01.001 DOI S0026286215000023 Publisher Item Identifier
Rights:	Copyright © 2015 Elsevier Inc. All rights reserved.
Divisions:	Schools > School of Science and Technology
Record created by:	Linda Sullivan
Date Added:	05 Jun 2018 07:46
Last Modified:	05 Jun 2018 07:46
URI:	https://irep.ntu.ac.uk/id/eprint/33813

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