Kakonen Sanna-Maria, Selander Katri S, Chirgwin John M, Yin Juan Juan, Burns Suzanne, Rankin Wayne A, Grubbs Barry G, Dallas Mark, Cui Yong, Guise Theresa A
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas 78245-3217, USA.
J Biol Chem. 2002 Jul 5;277(27):24571-8. doi: 10.1074/jbc.M202561200. Epub 2002 Apr 18.
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.
转化生长因子（TGF）-β促进乳腺癌向骨转移。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，将表达组成型活性TGF-β I型受体的MDA-MB-231乳腺癌细胞接种到小鼠体内。用PTHrP中和抗体治疗小鼠可大大减少溶骨性骨转移。抗体治疗的小鼠中破骨细胞较少，肿瘤面积显著减小。TGF-β可通过Smad和丝裂原活化蛋白（MAP）激酶途径发出信号。野生型Smad2、Smad3或Smad4的稳定转染增加了TGF-β刺激的PTHrP分泌，而显性负性Smad2、Smad3或Smad4仅部分降低了TGF-β刺激的PTHrP分泌。当用多种蛋白激酶抑制剂处理细胞时，只有p38 MAP激酶途径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激酶抑制的联合作用导致TGF-β刺激的PTHrP产生完全受到抑制。此外，用TGF-β处理MDA-MB-231细胞导致p38 MAP激酶迅速磷酸化。因此，p38 MAP激酶途径似乎是TGF-β非Smad依赖性信号传导的主要组成部分，可能为抗溶骨治疗提供一个新的分子靶点。
