Diverse effects of zinc on NF-κB and AP-1 transcription factors:: implications for prostate cancer progression
Diverse effects of zinc on NF-κB and AP-1 transcription factors:: implications for prostate cancer progression
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DOI：
10.1093/carcin/bgl034
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发表时间：
2006-10-01
期刊：
影响因子：
4.7
通讯作者：
Kolenko, Vladimir M.
中科院分区：
文献类型：
--
作者：
Uzzo, Robert G.;Crispen, Paul L.;Kolenko, Vladimir M.
核因子-kappaB (NF-kappa B) 和 AP-1 核转录因子调节涉及肿瘤生长、转移和血管生成的多个基因的表达；然而，每个因素对癌症发生和进展的相对贡献尚未确定。前列腺癌发生涉及正常积锌上皮细胞转化为不积锌的恶性细胞。鉴于 NF-kappa B 和 AP-1 的激活与前列腺癌的发生和生长有关，我们测试了补锌对这些重要转录因子的相对影响。在此，我们证明生理水平的锌会抑制 NF-κ B，但会增强 DU-145 和 PC-3 人前列腺癌细胞中 AP-1 的活性。此外，我们还发现，锌与膜渗透性锌螯合剂 N,N,N',N',-四(2-吡啶基甲基)乙二胺 (TPEN) 的螯合消除了这种效应。我们通过证明补锌诱导调节 AP-1 和 NF-kappa B 激活的三个主要 MAPK 亚家族成员（ERK 1/2、JNK 和 p38）的磷酸化，同时阻断 TNF-α 介导的抑制性亚基 I kappa B α 降解和前列腺癌细胞中 RelA 的核转位，进一步提出了这一观察结果的潜在机制。 VEGF、IL-6、IL-8 和 MMP-9 是主要的促血管生成和促转移分子，其启动子区域包含 NF-κ B 和 AP-1 的结合位点。这些细胞因子与前列腺癌的负面预后特征相关。我们证明用锌处理人前列腺癌细胞系可降低 VEGF、IL-6、IL-8 和 MMP-9 的表达。我们进一步表明，锌可降低细胞间粘附分子-1 的表达，并在功能上抑制肿瘤细胞的侵袭和粘附。因此，补充锌抑制 NF-κ B 的能力取代了锌介导的 AP-1 家族成员的激活。细胞内锌水平的上调可能对抑制恶性细胞的血管生成和转移潜力具有重要意义，主要是通过抑制 NF-κ B 信号传导。
Nuclear factor-kappaB (NF-kappa B) and AP-1 nuclear transcriptional factors regulate expression of multiple genes involved in tumor growth, metastasis and angiogenesis; however, the relative contribution of each factor to cancer initiation and progression has not been established. Prostate carcinogenesis involves transformation of normal zinc-accumulating epithelial cells to malignant cells that do not accumulate zinc. Whereas activation of both NF-kappa B and AP-1 has been implicated in prostate cancer development and growth, we tested the relative effects of zinc supplementation on these important transcriptional factors. Herein, we demonstrate that physiological levels of zinc inhibit NF-kappa B but augment activities of AP-1 in DU-145 and PC-3 human prostate cancer cells. Additionally, we show that chelation of zinc with membrane-permeable zinc chelator, N,N,N',N',-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) abolishes this effect. We further propose a potential mechanism for this observation by demonstrating that zinc supplementation induces phosphorylation of the members of three major MAPK subfamilies regulating AP-1 and NF-kappa B activation (ERK 1/2, JNK and p38) while blocking TNF-alpha-mediated degradation of the inhibitory subunit I kappa B alpha and nuclear translocation of RelA in prostate cancer cells. VEGF, IL-6, IL-8 and MMP-9 are major pro-angiogenic and pro-metastatic molecules whose promoter regions contain binding sites for both NF-kappa B and AP-1. These cytokines have been associated with negative prognostic features in prostate cancer. We demonstrate that treatment of human prostate cancer cell lines with zinc reduces expression of VEGF, IL-6, IL-8 and MMP-9. We further show that zinc reduces expression of intercellular adhesion molecule-1 and functionally suppresses tumor cell invasiveness and adhesion. Therefore, the ability of zinc supplementation to inhibit NF-kappa B supercedes zinc-mediated activation of AP-1 family members. Upregulation of intracellular zinc levels may have important implications for inhibiting the angiogenic and metastatic potentials of malignant cells, predominantly through suppression of NF-kappa B signaling.