Depletion of intracellular zinc increases expression of tumorigenic cytokines VEGF, IL-6 and IL-8 in prostate cancer cells via NF-kappaB-dependent pathway.
Depletion of intracellular zinc increases expression of tumorigenic cytokines VEGF, IL-6 and IL-8 in prostate cancer cells via NF-kappaB-dependent pathway.
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DOI：
10.1002/pros.20810
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发表时间：
2008-09-15
期刊：
影响因子：
2.8
通讯作者：
Kolenko, Vladimir M.
中科院分区：
文献类型：
--
作者：
Golovine, Konstantin;Uzzo, Robert G.;Makhov, Peter;Crispen, Paul L.;Kunkle, David;Kolenko, Vladimir M.
锌的积累在前列腺恶性肿瘤的早期减少，并在向非依赖性生长的进展过程中继续下降。相反，NF-κB活性的组成性水平在前列腺细胞向更大的致瘤潜能进展期间增加。我们以前曾报道过生理水平的锌抑制前列腺癌细胞中NF-κB的活性，并减少促血管生成和促转移细胞因子VEGF、IL-6、IL-8和MMP-9的表达，这些细胞因子与前列腺癌的不良预后特征相关。用原子吸收光谱法检测细胞内锌水平。用TransAm和荧光素酶报告基因检测NF-κB活性，Western Blot检测p50核转位。ELISA法检测VEGF、IL-6和IL-8水平。在雄激素非依赖性PC-3和DU-145前列腺癌细胞中，由膜渗透性锌螯合剂N，N，N '，N'-四（2-吡啶甲基）-乙二胺（TPEN）诱导的选择性锌缺乏增加了NF-κB的活化，并上调了NF-κB控制的促血管生成和促转移细胞因子VEGF、IL-6和IL-8的表达。用IκBα显性突变腺病毒预孵育可有效阻断缺锌细胞中这些细胞因子的表达，表明观察到的效应是NF-κB依赖性的。我们的研究结果表明，锌缺乏可能通过增加NF-κB依赖性促肿瘤细胞因子的表达而促进肿瘤进展。
Zinc accumulation diminishes early in the course of prostate malignancy and continues to decline during progression toward hormone-independent growth. In contrast, constitutive levels of NF-κB activity increase during progression of prostate cells toward greater tumorigenic potential. We have reported previously that physiological levels of zinc suppress NF-κB activity in prostate cancer cells and reduce expression of pro-angiogenic and pro-metastatic cytokines VEGF, IL-6, IL-8, and MMP-9 associated with negative prognostic features in prostate cancer. Intracellular zinc levels were examined by Atomic Absorption Spectroscopy. NF-κB activity was examined by TransAm and Luciferase reporter assays, and Western Blot analysis of p50 nuclear translocation. VEGF, IL-6 and IL-8 levels were assessed by ELISA. Selective zinc deficiency induced by the membrane-permeable zinc chelator N,N,N’,N’-tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN) increases activation of NF-κB and up-regulates expression of the NF-κB controlled pro-angiogenic and pro-metastatic cytokines VEGF, IL-6 and IL-8 in androgen-independent PC-3 and DU-145 prostate cancer cells. Pre-incubation with IκBα dominant mutant adenovirus efficiently blocks expression of these cytokines in zinc deficient cells indicating that the observed effects are NF-κB dependent. Our findings suggest that zinc deficiency may contribute to the tumor progression via augmented expression of the NF-κB dependent pro-tumorigenic cytokines.
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