Inhibitory effects of cyclosporin A on calcium mobilization-dependent interleukin-8 expression and invasive potential of human glioblastoma U251MG cells
Inhibitory effects of cyclosporin A on calcium mobilization-dependent interleukin-8 expression and invasive potential of human glioblastoma U251MG cells
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DOI：
10.1038/sj.onc.1207778
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发表时间：
2004-09-09
期刊：
影响因子：
8
通讯作者：
Seo, H
中科院分区：
文献类型：
--
作者：
Wakabayashi, K;Kambe, F;Seo, H
胶质母细胞瘤产生的白细胞介素 (IL)-8 被认为有助于其自身的增殖和进展。由于各种外部刺激已被证明会增加胶质瘤细胞中的细胞内 Ca2+，因此我们研究了 Ca2+ 动员依赖性 IL-8 表达以及钙调神经磷酸酶 (Cn) 抑制剂环孢菌素 A (CsA) 对人胶质母细胞瘤 U251MG 细胞的表达和侵袭潜力的影响。 Ca2+-离子载体和佛波醇-肉豆蔻酸酯-乙酸酯 (A23187/PMA) 联合治疗可增加 IL-8 mRNA 和蛋白质水平。这种增加被 CsA 和另一种 Cn 抑制剂 FK506 抑制。荧光素酶报告基因测定和电泳迁移率变动测定表明，含有 p65 的核因子 kappaB 的激活对于 A23187/PMA 依赖性 IL-8 启动子激活至关重要。 CsA 通过减弱 IkappaB-alpha 降解来抑制启动子活性。 U251MG 细胞表达 IL-8 受体 CXCR-1 和 -2，Matrigel 侵袭测定表明，CsA 可能通过抑制 IL-8 的产生来减弱 A23187/PMA 依赖性的侵袭潜力刺激。此外，CsA 还可抑制 IL-8 依赖性增殖。总而言之，这些结果证明了 CsA 对胶质母细胞瘤细胞功能的新型抑制作用，表明 CsA 作为神经胶质瘤治疗的潜在治疗佐剂。
Interleukin (IL)-8 produced from glioblastoma is suggested to contribute to its own proliferation and progression. Since various external stimuli have been shown to increase intracellular Ca2+ in glioma cells, we investigated Ca2+ mobilization-dependent IL-8 expression and effect of cyclosporin A (CsA), an inhibitor of calcineurin (Cn), on the expression and invasive potential of human glioblastoma U251MG cells. Combined treatment with Ca2+-ionophore and phorbol-myristate-acetate (A23187/PMA) increased IL-8 mRNA and protein levels. This increase was suppressed by CsA and by another Cn inhibitor FK506. Luciferase reporter gene assay and electrophoretic mobility shift assay revealed that activation of p65-containing nuclear factor-kappaB was essential for A23187/PMA-dependent activation of IL-8 promoter. CsA suppressed the promoter activity by attenuating IkappaB-alpha degradation. U251MG cells expressed IL-8 receptors CXCR-1 and -2, and Matrigel invasion assay revealed that CsA attenuated A23187/PMA-dependent stimulation of invasive potential, probably by inhibiting IL-8 production. In addition, IL-8-dependent proliferation was also suppressed by CsA. Taken together, these results demonstrate the novel inhibitory effects of CsA on glioblastoma cell functions, suggesting CsA as a potential therapeutic adjuvant for glioma treatment.