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p38 MAPK regulates the Wnt inhibitor Dickkopf-1 in osteotropic prostate cancer cells

机译：p38 MAPK调节骨增生性前列腺癌细胞中的Wnt抑制剂Dickkopf-1

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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.
机译：Wnt抑制剂Dickkopf-1（DKK-1）已通过抑制成骨细胞发生与骨转移性前列腺癌中骨转移的发生有关。在晚期前列腺癌中，P38丝裂原激活的蛋白激酶（MAPK）活性也失调。然而，p38 MAPK信号转导对DKK-1的影响仍然未知。小分子抑制剂（doramapimod，LY2228820和SB202190）抑制溶骨性PC3细胞中p38 MAPK信号转导抑制了DKK-1表达，而茴香霉素激活p38 MAPK则增加了DKK-1。通过用siRNA靶向单个p38 MAPK同工型进一步解剖显示，在调节DKK-1中，MAPK11的作用比MAPK14和MAPK12强。此外，主要具有溶骨性表型的前列腺癌细胞产生了足够量的DKK-1，以抑制Wnt3a诱导的C2C12细胞成骨细胞分化。通过使用特异性抗体中和DKK-1可以直接阻断这种抑制作用，也可以通过阻断p38 MAPK间接阻断这种抑制作用。此外，人前列腺癌中的组织表达揭示了p38 MAPK和DKK-1表达之间的相关性，与正常组织相比，其在肿瘤中的表达更高。这些结果表明，p38 MAPK调节前列腺癌中的DKK-1，并可能在溶骨性前列腺癌中提供潜在的靶标。

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