Abstract
It is becoming increasingly recognized that hydrogen peroxide (HP) plays a role in cell proliferation and migration. In the present study we found that exogenous HP significantly induced human prostate cancer LNCaP cell proliferation and migration. Heparin affin regulatory peptide (HARP) seems to be involved in the stimulatory effect of HP, because the latter had no effect on stably transfected LNCaP cells that did not express HARP. Moreover, HP significantly increased HARP mRNA and protein amounts in a concentration- and time-dependent manner. Curcumin and activator protein-1 (AP-1) decoy oligonucleotides abrogated both HP-induced HARP expression and LNCaP cell proliferation and migration. HP increased luciferase activity of the 5'-flanking region of the HARP gene introduced in a reporter gene vector, an effect that was abolished when even one of the two putative AP-1 binding sites of the HARP promoter was mutated. The effect of HP seems to be due to the binding of Fra-1, JunD, and phospho-c-Jun to the HARP promoter. These results support the notion that HARP is important for human prostate cancer cell proliferation and migration, establish the role of AP-1 in the up-regulation of HARP expression by low concentrations of HP, and characterize the AP-1 dimers involved.
Highlights
Heparin affin regulatory peptide (HARP), called pleiotrophin or heparin-binding growth-associated molecule, is an 18-kDa secreted growth factor that displays high affinity for heparin
The aim of the present study was to determine the effect of low concentrations of hydrogen peroxide (HP) on human prostate cancer LNCaP cell proliferation and migration and to investigate whether HARP is involved in these effects
Effect of HP on LNCaP Cell Proliferation and Migration—We have recently shown that HP increases angiogenesis in vivo [11] and human endothelial cell proliferation and migration in vitro [12]
Summary
Heparin affin regulatory peptide (HARP), called pleiotrophin or heparin-binding growth-associated molecule, is an 18-kDa secreted growth factor that displays high affinity for heparin. A growing body of evidence indicates that HARP is involved in cell proliferation, migration, and differentiation and plays a significant role in several cellular processes [5, 6]. When the promoter region of HARP gene was first cloned in 1992, no binding sites for known general transcription factors in the immediate promoter region were detected, two potential AP-1 sites were found in the distal 5Ј-promoter region [9]. The aim of the present study was to determine the effect of low concentrations of HP on human prostate cancer LNCaP cell proliferation and migration and to investigate whether HARP is involved in these effects. Our results argue for an HP-induced, AP-1-dependent transcriptional up-regulation of the human HARP gene, resulting in increased LNCaP cell proliferation and migration
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