Polytarchou Christos, Hatziapostolou Maria, Papadimitriou Evangelia
Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, GR26504 Patras, Greece.
J Biol Chem. 2005 Dec 9;280(49):40428-35. doi: 10.1074/jbc.M505120200. Epub 2005 Sep 30.
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.
越来越多的人认识到过氧化氢（HP）在细胞增殖和迁移中发挥作用。在本研究中，我们发现外源性HP显著诱导人前列腺癌LNCaP细胞的增殖和迁移。肝素亲和调节肽（HARP）似乎参与了HP的刺激作用，因为HP对不表达HARP的稳定转染LNCaP细胞没有影响。此外，HP以浓度和时间依赖性方式显著增加HARP mRNA和蛋白质的量。姜黄素和激活蛋白-1（AP-1）诱饵寡核苷酸消除了HP诱导的HARP表达以及LNCaP细胞的增殖和迁移。HP增加了报告基因载体中引入的HARP基因5'侧翼区域的荧光素酶活性，当HARP启动子的两个推定AP-1结合位点中的任何一个发生突变时，这种效应就会被消除。HP的作用似乎是由于Fra-1、JunD和磷酸化c-Jun与HARP启动子的结合。这些结果支持了HARP对人前列腺癌细胞增殖和迁移很重要的观点，确立了AP-1在低浓度HP上调HARP表达中的作用，并鉴定了所涉及的AP-1二聚体。
