Inhibiting checkpoint kinase 1 protects bone from bone resorption by mammary tumor in a mouse model.
Inhibiting checkpoint kinase 1 protects bone from bone resorption by mammary tumor in a mouse model.
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DOI：
10.18632/oncotarget.24286
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发表时间：
2018-02-06
期刊：
影响因子：
--
通讯作者：
Yokota H
中科院分区：
文献类型：
--
作者：
Liu S;Liu Y;Minami K;Chen A;Wan Q;Yin Y;Gan L;Xu A;Matsuura N;Koizumi M;Liu Y;Na S;Li J;Nakshatri H;Li BY;Yokota H
DNA损伤反应在肿瘤生长中起关键作用，但对其在骨代谢中的潜在作用知之甚少。我们采用Chk 1的选择性抑制剂，并检查其对乳腺肿瘤细胞的增殖和迁移以及成骨细胞和破骨细胞的发育的影响。此外，使用骨转移的小鼠模型，我们评估了Chk 1抑制剂对骨质量的影响。Chk 1抑制剂在体外阻断肿瘤细胞的增殖、存活和迁移，并通过下调NFATc 1抑制骨吸收破骨细胞的发育。在小鼠模型中，Chk 1抑制剂减少了溶骨性病变，并防止了股骨和胫骨的机械弱化。RNA-seq表达数据分析表明，观察到的效应是通过调节真核翻译起始因子2 α、内质网应激、S100蛋白和骨重塑相关基因介导的。我们的研究结果表明，在不添加DNA损伤剂的情况下靶向Chk 1信号传导可能会保护骨免受降解，同时抑制肿瘤生长和迁移。
DNA damage response plays a critical role in tumor growth, but little is known about its potential role in bone metabolism. We employed selective inhibitors of Chk1 and examined their effects on the proliferation and migration of mammary tumor cells as well as the development of osteoblasts and osteoclasts. Further, using a mouse model of bone metastasis we evaluated the effects of Chk1 inhibitors on bone quality. Chk1 inhibitors blocked the proliferation, survival, and migration of tumor cells in vitro and suppressed the development of bone-resorbing osteoclasts by downregulating NFATc1. In the mouse model, Chk1 inhibitor reduced osteolytic lesions and prevented mechanical weakening of the femur and tibia. Analysis of RNA-seq expression data indicated that the observed effects were mediated through the regulation of eukaryotic translation initiation factor 2 alpha, stress to the endoplasmic reticulum, S100 proteins, and bone remodeling-linked genes. Our findings suggest that targeting Chk1 signaling without adding DNA damaging agents may protect bone from degradation while suppressing tumor growth and migration.
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