Abstract
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.
Highlights
Osteolytic, where bone loss and destruction are increased
The role of DKK-1 in cancer remains controversial with claims of both tumor-suppressor and promotor roles depending on the cancer type,[11,12,13,14,15] it has been convincingly demonstrated that elevated levels are responsible for the induction of osteolytic lesions in bone-seeking cancers such as multiple myeloma and breast cancer.[16,17,18,19]
We have previously shown that DKK-1 is elevated in the serum of prostate cancer patients and high levels of serum DKK-1 were associated with a poorer prognosis.[20]
Summary
Osteolytic, where bone loss and destruction are increased. In the clinical setting, histological examinations often show that metastatic lesions arising from solid tumors are heterogeneous.[5]. One key feature of osteolytic activity in bone metastases is an impaired function of the osteoblasts, caused by tumorderived factors. Wnt signaling regulates osteoblast differentiation and function and is important for bone homeostasis.[9] DKK-1 as a Wnt inhibitor negatively regulates osteoblast differentiation.[10] the role of DKK-1 in cancer remains controversial with claims of both tumor-suppressor and promotor roles depending on the cancer type,[11,12,13,14,15] it has been convincingly demonstrated that elevated levels are responsible for the induction of osteolytic lesions in bone-seeking cancers such as multiple myeloma and breast cancer.[16,17,18,19] we have previously shown that DKK-1 is elevated in the serum of prostate cancer patients and high levels of serum DKK-1 were associated with a poorer prognosis.[20] In addition, elevated levels of DKK-1 in prostate bone metastases have been associated with a poorer survival.[21]. MAPK14 and MAPK11 are the two most discussed in cancer research to date, being the closest related in structure, activity and sensitivity to inhibitors.[22]
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