DKK1 activates noncanonical NF-κB signaling via IL-6-induced CKAP4 receptor in multiple myeloma.

Abstract Proteasome inhibitors, such as bortezomib, represent the key elements in chemotherapy regimens for multiple myeloma, whereas acquired chemoresistance and ultimately relapse remain a major obstacle. In the current study, we screened differently expressed cytokines in bortezomib-resistant MM cells, and found that DKK1 level was remarkably augmented, while CD138 level was significantly suppressed. DKK1 in vitro specifically enhanced the resistance of myeloma cells to bortezomib treatment, and excessive DKK1 drove CD138 downregulation via inhibition of canonical Wnt signaling. Notably, DKK1 mainly induced drug resistance in multiple myeloma cells via the receptor of CKAP4. Mechanistically, CKAP4 transduced DKK1 signal and evoked NF-κB pathway through recruiting and preventing the CAND1 from hampering the assembly of E3 ligase mediated ubiquitination of IκBα. In addition, we found that IL-6 stimulated CKAP4 expression to generate drug resistance, and disturbance of DKK1-CKAP4 axis improved sensitivity to BTZ treatment of multiple myeloma and attenuated bone destruction in a mouse model. Collectively, our study revealed previously not identified role of DKK1 in myeloma drug resistance via Wnt signaling dependent and independent manners, and clarified the importance of antagonism of DKK1-IL-6 loop in bone marrow microenvironment.