Differential regulation of survivin expression and apoptosis by vitamin D3 compounds in two isogenic MCF-7 breast cancer cell sublines
Differential regulation of survivin expression and apoptosis by vitamin D3 compounds in two isogenic MCF-7 breast cancer cell sublines
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DOI：
10.1038/sj.onc.1208330
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发表时间：
2005-02-17
期刊：
影响因子：
8
通讯作者：
Brattain, MG
中科院分区：
文献类型：
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作者：
Li, FZ;Ling, X;Brattain, MG
尽管生存素和维生素D-3（VD 3）介导的细胞生长抑制和凋亡的抗凋亡功能已被广泛研究，但尚不清楚生存素是否在VD 3化合物介导的细胞生长抑制和凋亡诱导中起作用。使用MCF-7乳腺癌细胞（对VD 3化合物敏感和耐药的MCF-7 E和MCF-7 L亚系）的同基因模型，我们发现VD 3化合物有效地下调VD 3敏感的MCF-7 E细胞中的存活素，这与VD 3诱导的细胞凋亡相关。相比之下，VD 3化合物不能下调VD 3抗性MCF-7 L细胞中的存活素，其显示出对VD 3诱导的细胞凋亡的抗性。然而，小干扰RNA（siRNA）抑制生存素的表达诱导细胞死亡本身，并进一步敏化VD 3诱导的MCF-7 L细胞凋亡，表明这些细胞不能响应VD 3是由于未能下调生存素。Survivin的强制表达不仅阻断了VD 3介导的G1期细胞聚集，而且增加了S期和G2/M期细胞群。VD 3处理在MCF-7 E细胞中迅速触发p38 MAPK信号传导的激活，但在MCF 7 L细胞中不触发。此外，抑制p38活化减弱了VD 3介导的存活素抑制，并部分挽救了VD 3诱导的细胞死亡。我们进一步表明，VD 3增加了TGF β 1和TGF β受体2的表达，阻断TGF β受体2的功能减少了VD 3化合物介导的生存素下调。因此，我们认为VD 3化合物诱导的生长抑制和凋亡诱导至少部分依赖于存活素通过VD 3诱导的TGF β信号传导和p38 MAPK通路的激活而下调。通过这些途径靶向生存素可能会导致癌症治疗的新应用。2004年12月20日在线发布。
Although both the antiapoptotic function of survivin and vitamin D-3 (VD3)-mediated cell growth inhibition and apoptosis have been extensively studied, it is not known whether survivin plays a role in VD3 compound-mediated cell growth inhibition and apoptosis induction. Using an isogenic model of MCF-7 breast adenocarcinoma cells (MCF-7E and MCF-7L sublines that are sensitive and resistant to VD3 compounds), we found that VD3 compounds effectively downregulated survivin in VD3-sensitive MCF-7E cells, which was associated with VD3-induced apoptosis. In contrast, VD3 compounds failed to downregulate survivin in VD3-resistant MCF-7L cells, which showed resistant to VD3-induced apoptosis. However, inhibition of survivin expression by small interfering RNA (siRNA) induced cell death per se and further sensitized VD3-induced apoptosis in MCF-7L cells, indicating that the inability of these cells to respond to VD3 is due to the failure to downregulate survivin. Forced expression of survivin not only blocked VD3-mediated G1 cell accumulation but also increased S and G2/M cell populations. VD3 treatment rapidly triggered the activation of p38 MAPK signaling in MCF-7E cells but not in MCF7L cells. Moreover, inhibition of p38 activation diminished VD3-mediated survivin inhibition and partially rescued VD3-induced cell death. We further showed that VD3 increased the expression of TGFbeta1 and TGFbeta receptor 2, and that blocking the function of TGFbeta receptor 2 diminished VD3 compound-mediated survivin downregulation. Thus, we propose that the VD3 compound-induced growth inhibition and apoptosis induction are at least partially dependent on survivin downregulation via VD3-induced TGFbeta signaling and the activation of p38 MAPK pathway. Targeting survivin through these pathways may lead to novel applications for cancer therapeutics. Published online 20 December 2004.