Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism
Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism
复制标题
DOI：
10.1158/1535-7163.mct-06-0684
复制
发表时间：
2007-06-01
影响因子：
5.7
通讯作者：
Niitsu, Yoshiro
中科院分区：
文献类型：
--
作者：
Kobune, Masayoshi;Chiba, Hiroki;Niitsu, Yoshiro
骨髓瘤细胞与骨髓基质细胞的黏附现在被认为在化疗耐药中起关键作用。然而，有关骨髓瘤细胞黏附介导的耐药(CAM-DR)的分子机制却知之甚少。在这项研究中，我们的兴趣集中在Wnt信号在CAM-DR中的含义上。我们首先对WNT家族在骨髓瘤细胞系中的表达进行了筛选，发现WNT3在所有被检测的骨髓瘤细胞中都过表达。高表达WNT3蛋白的KMS-5和ARH77与人骨髓基质细胞紧密结合，在这些骨髓瘤细胞系中观察到(3-catenin和GTP结合的RhoA)的聚集。相反，适度表达WNT3蛋白的RPM18226和MM1S与人骨髓基质的粘附性较弱。然后，我们研究了WNT3的表达与基质细胞的粘附性和骨髓瘤细胞的CAM-DR之间的相关性。KMS-5和ARH-77对阿霉素表现出明显的CAM-DR。抗整合素抗体、抗整合素作为抗体和Wnt受体竞争对手，分泌FrizzledR相关蛋白-1和Rho激酶抑制剂Y27632，但不能被规范信号的特异性抑制物(Dickkopf-1)抑制，表明Wnt介导的依赖整合素α(6)/β(1)(VLA-6)介导的CAMDR与基质细胞的附着是由Wnt/RhoA/Rho激酶途径信号诱导的。WNT3小干扰RNA转移到KMS-5后，该CAM-DR也显著降低。这些结果表明，WNT3通过骨髓瘤细胞的Wnt/RhoA/ROCK途径以自分泌的方式参与VLA-6介导的CAM-DR。因此，WNT3信号通路有望成为克服骨髓瘤细胞CAM-DR的分子靶点。
Adhesion of myeloma cells to bone marrow stromal cells is now considered to play a critical role in chemoresistance. However, little is known about the molecular mechanism governing cell adhesion-mediated drug resistance (CAM-DR) of myeloma cells. In this study, we focused our interests on the implication of the Wnt signal in CAM-DR. We first screened the expression of Wnt family in myeloma cell lines and found that Wnt3 was overexpressed in all the myeloma cells examined. KMS-5 and ARH77, which highly expressed Wnt3 protein, tightly adhered to human bone marrow stromal cells, and accumulation of (3-catenin and GTP-bounded RhoA was observed in these myeloma cell lines. Conversely, RPM18226 and MM1S, which modestly expressed Wnt3 protein, rather weakly adhered to human bone marrow stromal. We then examined the relevance of Wnt3 expression to adhesive property to stromal cells and to CAM-DR of myeloma cells. KMS-5 and ARH-77 exhibited apparent CAM-DR against doxorubicin. This CAM-DR was significantly reduced by anti-integrin (it antibody, antiintegrin as antibody and a Wnt-receptor competitor, secreted Frizzled-related protein-1, and Rho kinase inhibitor Y27632, but not by the specific inhibitor of canonical signaling (Dickkopf-1), indicating that Wnt-mediated CAMDR that is dependent on integrin alpha(6)/beta(1) (VLA-6)-mediated attachment to stromal cells is induced by the Wnt/RhoA/Rho kinase pathway signal. This CAM-DR was also significantly reduced by Wnt3 small interfering RNA transfer to KMS-5. These results indicate that Wnt3 contributes to VLA-6-mediated CAM-DR via the Wnt/RhoA/ROCK pathway of myeloma cells in an autocrine manner. Thus, the Wnt3 signaling pathway could be a promising molecular target to overcome CAM-DR of myeloma cells.