DKK1 activates noncanonical NF-κB signaling via IL-6-induced CKAP4 receptor in multiple myeloma
DKK1 activates noncanonical NF-κB signaling via IL-6-induced CKAP4 receptor in multiple myeloma
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DOI：
10.1182/bloodadvances.2021004315
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发表时间：
2021-09-24
期刊：
影响因子：
7.5
通讯作者：
Liu, Zhiqiang
中科院分区：
文献类型：
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作者：
Li, Xin;Wang, Jingjing;Liu, Zhiqiang
蛋白酶体抑制剂，如硼替佐米(BTZ)，是多发性骨髓瘤(MM)化疗方案中的关键因素，而获得性化疗耐药和最终复发仍是主要障碍。在本研究中，我们筛选了在耐药的MM细胞中差异表达的细胞因子，发现Dickkopf-1(Dkk1)水平显著上调，而CD138水平显著抑制。在体外，Dkk1特异性地增强了骨髓瘤细胞对Bortezomib的耐药性，过量的Dkk1通过抑制规范的Wnt信号而导致CD138下调。值得注意的是，Dkk1主要通过CKAP4受体诱导MM细胞耐药。在机制上，CKAP4通过募集和阻止cullin相关和nedylated 1阻碍E3连接酶介导的I kappaBα泛素化组装，从而转导Dkk1信号并激活NF-kappaB途径。此外，我们还发现，白介素6(IL-6)刺激CKAP4的表达以产生耐药性，并且Dkk1-CKAP4轴的紊乱提高了对BTZ治疗MM的敏感性，并在小鼠模型中减轻了骨破坏。综上所述，本研究通过Wnt信号依赖和独立的方式揭示了Dkk1在骨髓瘤耐药中的未知作用，阐明了Dkk1-IL-6环拮抗作用在骨髓微环境中的重要性。
Proteasome inhibitors, such as bortezomib (BTZ), represent the key elements in chemotherapy regimens for multiple myeloma (MM), 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 Dickkopf-1 (DKK1) level was remarkably augmented, whereas 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 MM cells via the receptor of CKAP4. Mechanistically, CKAP4 transduced DKK1 signal and evoked NF-kappa B pathway through recruiting and preventing cullin associated and neddylation dissociated 1 from hampering the assembly of E3 ligase-mediated ubiquitination of I kappa B alpha. In addition, we found that interleukin-6 (IL-6) stimulated CKAP4 expression to generate drug resistance, and disturbance of DKK1-CKAP4 axis improved sensitivity to BTZ treatment of MM and attenuated bone destruction in a mouse model. Collectively, our study revealed the previously unidentified 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.