Heparin Affin Regulatory Peptide/Pleiotrophin Mediates Fibroblast Growth Factor 2 Stimulatory Effects on Human Prostate Cancer Cells

Maria Hatziapostolou,Christos Polytarchou,Panagiotis Katsoris,Jose Courty,Evangelia Papadimitriou

doi:10.1074/jbc.m607104200

Abstract

Fibroblast growth factor 2 (FGF2) is a pleiotropic growth factor that has been implicated in prostate cancer formation and progression. In the present study we found that exogenous FGF2 significantly increased human prostate cancer LNCaP cell proliferation and migration. Heparin affin regulatory peptide (HARP) or pleiotrophin seems to be an important mediator of FGF2 stimulatory effects, since the latter had no effect on stably transfected LNCaP cells that did not express HARP. Moreover, FGF2, through FGF receptors (FGFRs), significantly induced HARP expression and secretion by LNCaP cells and increased luciferase activity of a reporter gene vector carrying the full-length promoter of HARP gene. Using a combination of Western blot analyses, as well as genetic and pharmacological inhibitors, we found that activation of FGFR by FGF2 in LNCaP cells leads to NAD(P)H oxidase-dependent hydrogen peroxide production, phosphorylation of ERK1/2 and p38, activation of AP-1, increased expression and secretion of HARP, and, finally, increased cell proliferation and migration. These results establish the role and the mode of activity of FGF2 in LNCaP cells and support an interventional role of HARP in FGF2 effects, providing new insights on the interplay among growth factor pathways within prostate cancer cells.

Highlights

Human prostate relies on a range of growth factors for its normal growth and development
Using a combination of Western blot analyses, as well as genetic and pharmacological inhibitors, we found that activation of FGF receptors (FGFRs) by Fibroblast growth factor 2 (FGF2) in LNCaP cells leads to NAD(P)H oxidase-dependent hydrogen peroxide production, phosphorylation of ERK1/2 and p38, activation of activator protein-1 (AP-1), increased expression and secretion of Heparin affin regulatory peptide (HARP), and, increased cell proliferation and migration
HARP Expression Is Required for FGF2-induced LNCaP Cell Proliferation and Migration—We initially studied the effect of FGF2 on the proliferation and migration of human prostate cancer LNCaP cells

Summary

Introduction

Human prostate relies on a range of growth factors for its normal growth and development. Inhibition of FGF2 expression has been associated with increased levels of vascular endothelial growth factor (VEGF) in poorly differentiated TRAMP prostate tumors, implying that other factors can at least partly overcome loss of FGF2 stimulation [7]. We have recently identified HARP as an important autocrine growth factor for the LNCaP prostate cancer cell line and as a paracrine growth factor implicated in prostate cancer cell-induced angiogenesis in vivo and in vitro [12]. The goal of this study was to evaluate the effect of FGF2 on human prostate cancer LNCaP cell proliferation and migration and investigate whether HARP is implicated in FGF2-mediated activation of LNCaP cells. Our data demonstrate an FGF2-induced H2O2-dependent HARP up-regulation, resulting in increased LNCaP cell proliferation and migration and suggest that H2O2 generation in response to FGFR stimulation originates from NAD(P)H oxidase activation and results in activator protein-1 (AP-1)-mediated HARP expression

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