Silibinin inhibits prostate cancer cells- and RANKL-induced osteoclastogenesis by targeting NFATc1, NF-κB, and AP-1 activation in RAW264.7 cells.
Silibinin inhibits prostate cancer cells- and RANKL-induced osteoclastogenesis by targeting NFATc1, NF-κB, and AP-1 activation in RAW264.7 cells.
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DOI：
10.1002/mc.21959
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发表时间：
2014-03
影响因子：
4.6
通讯作者：
Agarwal, Rajesh
中科院分区：
文献类型：
--
作者：
Kavitha, Chandagirikoppal V.;Deep, Gagan;Gangar, Subhash C.;Jain, Anil K.;Agarwal, Chapla;Agarwal, Rajesh
目前，针对骨转移性前列腺癌（PCA）的治疗选择有限，骨转移性前列腺癌是PCA患者的高死亡率和发病率的主要原因。破骨细胞生成增强是骨微环境中与转移性PCA相关的基本特征。水飞蓟宾是一种有效的化学预防剂，目前正在PCA患者中进行II期临床试验，但其对PCA细胞诱导的破骨细胞生成的疗效在很大程度上尚不清楚。因此，在这里，我们使用人PCA（PC 3 MM 2、PC 3和C4-2B）和鼠巨噬细胞RAW 264.7细胞检测了水飞蓟宾对PCA细胞诱导的破骨细胞生成的作用。我们还评估了水飞蓟宾对核因子B配体受体激活因子（RANKL）诱导的与RAW 264.7细胞中破骨细胞分化相关的信号传导的影响。此外，我们分析了水飞蓟宾对PCA细胞中骨模拟生物标志物的影响。结果显示，水飞蓟宾（30-90 μM）通过调节多种细胞因子（IGF-1、TGF-β、TNF-α、I-TAC、M-CSF、G-CSF和GM-CSF等）的表达，抑制PCA细胞诱导的RAW264.7细胞破骨细胞活性和分化。在破骨细胞生成中很重要。此外，在RAW264.7细胞中，水飞蓟宾降低了RANKL诱导的NFATc 1表达和核定位，NFATc 1被认为是破骨细胞生成的主要调节因子。此外，水飞蓟宾降低RANKL诱导的NFATc 1及其调节因子NF-κB和AP 1的DNA结合活性，以及破骨细胞特异性标志物（TRAP、OSCAR和Cathepsin K）的蛋白表达。重要的是，水飞蓟宾还降低了细胞培养物（PC 3和C4-2B细胞）和/或PC 3肿瘤中的骨模拟生物标志物（RANKL、Runx 2、骨钙素和PTHrP）的表达。总之，我们的研究结果表明，水飞蓟宾抑制PCA细胞诱导的破骨细胞生成，表明水飞蓟宾可能是有用的临床骨转移PCA。
Currently, there are limited therapeutic options against bone metastatic prostate cancer (PCA), which is primarily responsible for high mortality and morbidity in PCA patients. Enhanced osteoclastogenesis is an essential feature associated with metastatic PCA in the bone microenvironment. Silibinin, an effective chemopreventive agent, is in phase II clinical trials in PCA patients but its efficacy against PCA cells-induced osteoclastogenesis is largely unknown. Accordingly, here we examined silibinin effect on PCA cells-induced osteoclastogenesis employing human PCA (PC3MM2, PC3 and C4-2B) and murine macrophage RAW264.7 cells. We also assessed silibinin effect on receptor activator of nuclear factor B ligand (RANKL)-induced signaling associated with osteoclast differentiation in RAW264.7 cells. Further, we analyzed silibinin effect on osteomimicry biomarkers in PCA cells. Results revealed that silibinin (30–90 μM) inhibits PCA cells-induced osteoclast activity and differentiation in RAW264.7 cells via modulating expression of several cytokines (IGF-1, TGF-β, TNF-α, I-TAC, M-CSF, G-CSF, and GM-CSF etc.) that are important in osteoclastogenesis. Additionally, in RAW264.7 cells, silibinin decreased the RANKL-induced expression and nuclear localization of NFATc1, which is considered the master regulator of osteoclastogenesis. Furthermore, silibinin decreased the RANKL-induced DNA binding activity of NFATc1 and its regulators NF-κB and AP1, and the protein expression of osteoclast specific markers (TRAP, OSCAR and Cathepsin K). Importantly, silibinin also decreased the expression of osteomimicry biomarkers (RANKL, Runx2, Osteocalcin and PTHrP) in cell culture (PC3 and C4-2B cells) and/or in PC3 tumors. Together, our findings showing that silibinin inhibits PCA cells-induced osteoclastogenesis, suggest that silibinin could be useful clinically against bone metastatic PCA.
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影响因子：
8
作者：
Agarwal, C;Singh, RP;Agarwal, R
通讯作者：
Agarwal, R
DOI：
10.1016/j.bbrc.2006.09.076
发表时间：
2006-11-17
影响因子：
3.1
作者：
Adamopoulos, Iannis E.;Xia, Zhidao;Athanasou, Nicholas A.
通讯作者：
Athanasou, Nicholas A.
影响因子：
7.3
作者：
Josson S;Matsuoka Y;Chung LW;Zhau HE;Wang R
通讯作者：
Wang R
影响因子：
4.9
作者：
Braun T;Zwerina J
通讯作者：
Zwerina J
影响因子：
3.4
作者：
Flaig, Thomas W.;Gustafson, Daniel L.;Glode, L. Michael
通讯作者：
Glode, L. Michael