Browne A J, Göbel A, Thiele S, Hofbauer L C, Rauner M, Rachner T D
Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Cell Death Dis. 2016 Feb 25;7(2):e2119. doi: 10.1038/cddis.2016.32.
The Wnt inhibitor Dickkopf-1 (DKK-1) has been associated with the occurrence of bone metastases in osteotropic prostate cancer by inhibiting osteoblastogenesis. P38 mitogen-activated protein kinase (MAPK) activity is also dysregulated in advanced prostate cancer. However, the impact of p38 MAPK signaling on DKK-1 remains unknown. Inhibition of p38 MAPK signaling in osteolytic PC3 cells by small molecule inhibitors (doramapimod, LY2228820 and SB202190) suppressed DKK-1 expression, whereas activation of p38 MAPK by anisomycin increased DKK-1. Further dissection by targeting individual p38 MAPK isoforms with siRNA revealed a stronger role for MAPK11 than MAPK14 and MAPK12 in the regulation of DKK-1. Moreover, prostate cancer cells with a predominantly osteolytic phenotype produced sufficient amounts of DKK-1 to inhibit Wnt3a-induced osteoblastic differentiation in C2C12 cells. This inhibition was blocked directly by neutralizing DKK-1 using a specific antibody and also indirectly by blocking p38 MAPK. Furthermore, tissue expression in human prostate cancer revealed a correlation between p38 MAPK and DKK-1 expression with higher expression in tumor compared with normal tissues. These results reveal that p38 MAPK regulates DKK-1 in prostate cancer and may present a potential target in osteolytic prostate cancers.
Wnt抑制剂Dickkopf-1（DKK-1）通过抑制成骨细胞生成，与亲骨性前列腺癌骨转移的发生相关。在晚期前列腺癌中，p38丝裂原活化蛋白激酶（MAPK）活性也失调。然而，p38 MAPK信号传导对DKK-1的影响尚不清楚。小分子抑制剂（多瑞帕明、LY2228820和SB202190）抑制溶骨性PC3细胞中的p38 MAPK信号传导可抑制DKK-1表达，而茴香霉素激活p38 MAPK则增加DKK-1。用小干扰RNA靶向单个p38 MAPK亚型进行的进一步分析表明，在DKK-1的调节中，MAPK11比MAPK14和MAPK12发挥更强的作用。此外，主要具有溶骨表型的前列腺癌细胞产生足够量的DKK-1，以抑制C2C12细胞中Wnt3a诱导的成骨细胞分化。使用特异性抗体中和DKK-1可直接阻断这种抑制作用，通过阻断p38 MAPK也可间接阻断。此外，人前列腺癌组织表达显示，与正常组织相比，肿瘤中p38 MAPK和DKK-1表达呈正相关，且肿瘤中表达更高。这些结果表明，p38 MAPK在前列腺癌中调节DKK-1，可能是溶骨性前列腺癌的一个潜在靶点。
