Src family kinase/abl inhibitor dasatinib suppresses proliferation and enhances differentiation of osteoblasts.
Src family kinase/abl inhibitor dasatinib suppresses proliferation and enhances differentiation of osteoblasts.
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DOI：
10.1038/onc.2010.73
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发表时间：
2010-06-03
期刊：
影响因子：
8
通讯作者：
Lin, S-H
中科院分区：
文献类型：
--
作者：
Lee, Y-C;Huang, C-F;Murshed, M.;Chu, K.;Araujo, J. C.;Ye, X.;deCrombrugghe, B.;Yu-Lee, L-Y;Gallick, G. E.;Lin, S-H
达沙替尼是一种Src家族激酶和Abl双重抑制剂，正在临床上测试其用于治疗前列腺癌骨转移。成骨细胞和前列腺癌细胞之间的双向相互作用在骨中前列腺癌的进展中至关重要，但达沙替尼对成骨细胞的影响尚不清楚。我们发现，达沙替尼抑制从小鼠颅骨分离的原代小鼠成骨细胞和永生化MC 3 T3-E1细胞系的增殖。在来自携带成骨细胞特异性胶原1 α1启动子-报告基因的Col-luc转基因小鼠的颅骨成骨细胞中，荧光素酶活性受到抑制。达沙替尼还抑制FGF-2诱导的成骨细胞增殖，但强烈促进成骨细胞分化，如通过刺激碱性磷酸酶活性、骨钙素分泌和成骨细胞矿化所反映的。为了确定达沙替尼如何阻断成骨细胞中的增殖信号传导，我们分析了成骨细胞中一组酪氨酸激酶的表达，包括Src、林恩、Fyn、Yes和Abl。在Src家族激酶中，只有Src被高水平激活。Abl在成骨细胞中低水平表达。Src-Y 419或Src-Y245的磷酸化被达沙替尼处理抑制。在成骨细胞中通过慢病毒shRNA敲低Src或Abl增强成骨细胞分化，表明达沙替尼通过抑制Src和Abl增强成骨细胞分化。
Dasatinib, a dual Src family kinase and Abl inhibitor, is being tested clinically for the treatment of prostate cancer bone metastasis. Bidirectional interactions between osteoblasts and prostate cancer cells are critical in the progression of prostate cancer in bone, but the effect of dasatinib on osteoblasts is unknown. We found that dasatinib inhibited proliferation of primary mouse osteoblasts isolated from mouse calvaria and the immortalized MC3T3-E1 cell line. In calvarial osteoblasts from Col-luc transgenic mice carrying osteoblast-specific Collagen1α1 promoter-reporter, luciferase activity was inhibited. Dasatinib also inhibited FGF-2–induced osteoblast proliferation, but strongly promoted osteoblast differentiation, as reflected by stimulation of alkaline phosphatase activity, osteocalcin secretion, and osteoblast mineralization. To determine how dasatinib blocks proliferative signaling in osteoblasts, we analyzed the expression of a panel of tyrosine kinases, including Src, Lyn, Fyn, Yes, and Abl, in osteoblasts. In the Src family kinases, only Src was activated at a high level. Abl was expressed at a low level in osteoblasts. Phosphorylation of Src-Y419 or Abl-Y245 was inhibited by dasatinib treatment. Knockdown of either Src or Abl by lenti shRNA in osteoblasts enhances osteoblast differentiation, suggesting that dasatinib enhances osteoblast differentiation through inhibition of both Src and Abl.
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DOI：
10.1073/pnas.90.10.4485
发表时间：
1993-05-15
影响因子：
11.1
作者：
LOWE, C;YONEDA, T;SORIANO, P
通讯作者：
SORIANO, P
影响因子：
11.2
作者：
Chen, Nanyue;Ye, Xiang-Cang;Lin, Sue-Hwa
通讯作者：
Lin, Sue-Hwa
影响因子：
11.2
作者：
Dai, JL;Keller, J;Keller, ET
通讯作者：
Keller, ET
影响因子：
8.8
作者：
Autzen, P;Robson, C N;Bjartell, A;Malcolm, A J;Johnson, M I;Neal, D E;Hamdy, F C
通讯作者：
Hamdy, F C
影响因子：
4.1
作者：
Fakhry, A;Ratisoontorn, C;Nah, HD
通讯作者：
Nah, HD