Overexpression of the zinc uptake transporter hZIP1 inhibits nuclear factor-kappaB and reduces the malignant potential of prostate cancer cells in vitro and in vivo.
Overexpression of the zinc uptake transporter hZIP1 inhibits nuclear factor-kappaB and reduces the malignant potential of prostate cancer cells in vitro and in vivo.
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DOI：
10.1158/1078-0432.ccr-08-0455
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发表时间：
2008-09-01
期刊：
影响因子：
--
通讯作者：
Kolenko VM
中科院分区：
文献类型：
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作者：
Golovine K;Makhov P;Uzzo RG;Shaw T;Kunkle D;Kolenko VM
与正常前列腺组织相比，前列腺癌组织中细胞内锌水平和锌摄取转运体hZIP1的表达显著下调。我们之前的研究已经证明，锌在体外可以抑制NF-κB的活性，降低前列腺癌细胞的恶性潜能。在这项研究中，我们研究了hZIP1过表达对体外和体内人前列腺癌细胞中NF-κB活性和致瘤潜能的功能影响。用Western blotting和荧光素酶测定法检测PC-3前列腺癌细胞株中NF-κB的活性。用ELISA法检测致瘤细胞因子的表达。采用原位末端标记法、黏附法和侵袭力试验评估肿瘤细胞的恶性潜能。使用异种移植模型评估了hZIP1过表达对体内前列腺癌进展的影响。在PC-3细胞中过表达hZIP1转运蛋白导致在生理水平的锌存在下对NF-κB活性的显著抑制。抑制NF-κB的同时，几种由NF-κB控制的促转移和抗凋亡因子的表达减少，并使细胞对依托泊苷和TRAIL介导的细胞死亡敏感。此外，在异种移植模型中，hZIP1转运体的过度表达导致前列腺癌生长的倒退。我们的结果表明，hZIP1的过表达通过抑制NF-κB依赖的通路而对前列腺癌细胞的恶性潜能产生功能影响，并支持hZIP1在前列腺癌中可能作为肿瘤抑制基因的概念。
Intracellular zinc levels and expression of the zinc uptake transporter, hZIP1, are markedly down-regulated in prostate adenocarcinomatous tissue compared with normal prostate tissue. Our previous studies have demonstrated that zinc inhibits NF-κB activity and reduces the malignant potential of prostate cancer cells in vitro. In this study, we investigate the functional impact of hZIP1 overexpression on NF-κB activity and tumorigenic potential in human prostate cancer cells in vitro and in vivo. NF-κB activity in PC-3 prostate cancer cells was examined by Western blotting and luciferase assay. ELISA was used to examine the expression of tumorigenic cytokines. TUNEL, adhesion, and invasiveness assays were used to assess the malignant potential of tumor cells. The impact of hZIP1 overexpression on prostate tumor progression in vivo was assessed using a xenograft model. Overexpression of the hZIP1 transporter in PC-3 cells results in significant inhibition of NF-κB activity in the presence of physiological levels of zinc. NF-κB inhibition coincides with a reduction in expression of several NF-κB controlled pro-metastatic and anti-apoptotic factors as well as sensitization of the cells to etoposide and TRAIL mediated cell death. Moreover, over-expression of the hZIP1 transporter induces regression of prostate tumor growth in a xenograft model. Our results demonstrate that hZIP1 overexpression has a functional impact on the malignant potential of prostate cancer cells via inhibition of NF-κB-dependent pathways and support the concept that hZIP1 may function as a tumor suppressor gene in prostate cancer.