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首页> 外文期刊>Molecular cancer therapeutics >Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism.
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Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism.

机译：Wnt3 / RhoA / ROCK信号通路以自分泌机制参与多发性骨髓瘤的粘附介导的耐药性。

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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 beta-catenin and GTP-bounded RhoA was observed in these myeloma cell lines. Conversely, RPMI8226 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 beta(1) antibody, anti-integrin alpha(6) 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 CAM-DR 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.
机译：现在认为骨髓瘤细胞与骨髓基质细胞的粘附在化学抗性中起关键作用。但是，关于控制骨髓瘤细胞的细胞粘附介导的耐药性（CAM-DR）的分子机制知之甚少。在这项研究中，我们将注意力集中在Wnt信号在CAM-DR中的含义。我们首先筛选了骨髓瘤细胞系中Wnt家族的表达，发现Wnt3在所有检查的骨髓瘤细胞中均过表达。高表达Wnt3蛋白的KMS-5和ARH77紧密粘附于人骨髓基质细胞，在这些骨髓瘤细胞系中观察到β-catenin和GTP结合的RhoA的积累。相反，适度表达Wnt3蛋白的RPMI8226和MM1S较弱地粘附于人骨髓基质。然后，我们检查了Wnt3表达与基质细胞和骨髓瘤细胞CAM-DR的粘附性的相关性。 KMS-5和ARH-77对阿霉素表现出明显的CAM-DR。抗整联蛋白beta（1）抗体，抗整联蛋白alpha（6）抗体和Wnt受体竞争剂，分泌的卷曲蛋白相关蛋白1和Rho激酶抑制剂Y27632显着降低了CAM-DR，但没有降低信号的特定抑制剂（Dickkopf-1），表明Wnt / Wnt介导依赖于整联蛋白α（6）/ beta（1）（VLA-6）介导的与基质细胞结合的Wnt介导的CAM-DR RhoA / Rho激酶途径信号。 Wnt3小干扰RNA转移到KMS-5时，CAM-DR也显着降低。这些结果表明，Wnt3通过自分泌方式经由骨髓瘤细胞的Wnt / RhoA / ROCK途径对VLA-6介导的CAM-DR有贡献。因此，Wnt3信号通路可能是一个有希望的分子靶点，以克服骨髓瘤细胞的CAM-DR。

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