1alpha,25-Dihydroxyvitamin D(3) antiproliferative actions involve vitamin D receptor-mediated activation of MAPK pathways and AP-1/p21(waf1) upregulation in human osteosarcoma.
1alpha,25-Dihydroxyvitamin D(3) antiproliferative actions involve vitamin D receptor-mediated activation of MAPK pathways and AP-1/p21(waf1) upregulation in human osteosarcoma.
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1α,25-二羟基维生素 D(3) 的抗增殖作用涉及维生素 D 受体介导的 MAPK 通路激活和人骨肉瘤中 AP-1/p21(waf1) 的上调。
DOI：
10.1016/j.canlet.2007.02.013
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发表时间：
2007
期刊：
影响因子：
9.7
通讯作者：
Zanello,LauraP
中科院分区：
文献类型：
--
作者：
Wu,Wei;Zhang,Xiaoyu;Zanello,LauraP
类固醇1α，25-二羟基维生素D3（1,25 d）在人骨肉瘤细胞中的抗增殖作用的分子机制目前仅部分了解。为了更好地了解1,25D在骨中的抗肿瘤特性，我们稳定地沉默了人骨肉瘤SaOS-2细胞系中维生素D受体（VDR）的表达。我们发现，仅在表达天然水平VDR蛋白的SaOS-2细胞中，1,25 d处理在3天后使细胞增殖降低了约25%，并参与了MAPK/AP-1/p21waf1通路的激活。持续（3天）和短暂（15分钟）1,25 d处理以非基因组vdr依赖的方式激活JNK和ERK1/2 MAPK信号。然而，只有持续暴露于激素导致p21上调和随后的细胞周期基因组控制。ERK1/2上游的MEK1/MEK2级联特异性阻断AP-1和p21的1,25 d激活以及随后的抗增殖作用，即使在核VDR存在时也是如此。我们得出结论，1,25 d诱导的人骨肉瘤细胞增殖抑制是通过持续激活非基因组VDR信号下游的JNK和MEK1/MEK2途径发生的，这导致c-Jun/c-Fos （AP-1）复合物的上调，从而调节p21waf1基因的表达。我们的研究结果表明，在MAP激酶激活水平上，1,25 d /VDR非基因组信号和基因组信号之间存在串扰，导致人骨肉瘤细胞增殖减少。
The molecular mechanisms underlying antiproliferative actions of the steroid 1α,25-dihydroxy vitamin D3(1,25D) in human osteosarcoma cells are known only partially. To better understand the signaling involved in 1,25D anti-tumorigenic properties in bone, we stably silenced vitamin D receptor (VDR) expression in the human osteosarcoma SaOS-2 cell line. We found that 1,25D treatment reduced cell proliferation by approximately 25% after 3 days only in SaOS-2 cells expressing native levels of VDR protein, and involved activation of MAPK/AP-1/p21waf1pathways. Both sustained (3 days) and transient (15min) 1,25D treatment activated JNK and ERK1/2 MAPK signaling in a nongenomic VDR-dependent manner. However, only sustained exposure to hormone led to upregulation of p21 and subsequent genomic control of the cell cycle. Specific blockade of MEK1/MEK2 cascade upstream from ERK1/2 abrogated 1,25D activation of AP-1 and p21, and subsequent antiproliferative effects, even in the presence of a nuclear VDR. We conclude that 1,25D-induced inhibition of human osteosarcoma cell proliferation occurs via sustained activation of JNK and MEK1/MEK2 pathways downstream of nongenomic VDR signaling that leads to upregulation of a c-Jun/c-Fos (AP-1) complex, which in turn modulates p21waf1gene expression. Our results demonstrate a cross-talk between 1,25D/VDR nongenomic and genomic signaling at the level of MAP kinase activation that leads to reduction of cell proliferation in human osteosarcoma cells.