Transforming growth factor-β stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways
Transforming growth factor-β stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways
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DOI：
10.1074/jbc.m202561200
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发表时间：
2002-07-05
影响因子：
4.8
通讯作者：
Guise, TA
中科院分区：
文献类型：
--
作者：
Käkönen, SM;Selander, KS;Guise, TA
转化生长因子（TGF）-β促进乳腺癌骨转移。为了确定溶骨因子甲状旁腺激素相关蛋白（PTHrP）是否是肿瘤对TGF-β反应的主要介质，将小鼠接种表达组成型活性TGF-β I型受体的MDA-MB-231乳腺癌细胞。用PTHrP中和抗体治疗小鼠大大降低了溶骨性骨转移。在抗体处理的小鼠中存在较少的破骨细胞和显著减小的肿瘤面积。TGF-β可以通过Smad和丝裂原活化蛋白（MAP）激酶途径发出信号。野生型Smad 2、Smad 3或Smad 4的稳定转染增加了TGF-β刺激的PTHrP分泌，而显性阴性Smad 2、Smad 3或Smad 4仅部分减少TGF-β刺激的PTHrP分泌。当细胞用各种蛋白激酶抑制剂处理时，只有p38 MAP激酶通路的特异性抑制剂显著降低了基础和TGF-β刺激的PTHrP产生。Smad显性负性阻断和p38 MAP激酶抑制的组合导致TGF-β刺激的PTHrP产生的完全抑制。此外，TGF-β处理MDA-MB-231细胞导致p38 MAP激酶快速磷酸化。因此，p38 MAP激酶途径似乎是TGF-β介导的Smad非依赖性信号传导的主要组成部分，并可能为抗溶骨性治疗提供新的分子靶点。
Transforming growth factor (TGF)-beta promotes breast cancer metastasis to bone. To determine whether the osteolytic factor parathyroid hormone-related protein (PTHrP) is the primary mediator of the tumor response to TGF-beta, mice were inoculated with MDA-MB-231 breast cancer cells expressing a constitutively active TGF-beta type I receptor. Treatment of the mice with a PTHrP-neutralizing antibody greatly decreased osteolytic bone metastases. There were fewer osteoclasts and significantly decreased tumor area in the antibody-treated mice. TGF-beta can signal through both Smad and mitogen-activated protein (MAP) kinase pathways. Stable transfection of wild-type Smad2, Smad3, or Smad4 increased TGF-beta-stimulated PTHrP secretion, whereas dominant-negative Smad2, Smad3, or Smad4 only partially reduced TGF-beta-stimulated PTHrP secretion. When the cells were treated with a variety of protein kinases inhibitors, only specific inhibitors of the p38 MAP kinase pathway significantly reduced both basal and TGF-beta-stimulated PTHrP production. The combination of Smad dominant-negative blockade and p38 MAP kinase inhibition resulted in complete inhibition of TGF-beta-stimulated PTHrP production. Furthermore, TGF-beta treatment of MDA-MB-231 cells resulted in a rapid phosphorylation of p38 MAP kinase. Thus, the p38 MAP kinase pathway appears to be a major component of Smad-independent signaling by TGF-beta and may provide a new molecular target for anti-osteolytic therapy.