文章：

刺激Toll样受体-1/2联合Velcade增加对人多发性骨髓瘤细胞的细胞毒性

Stimulation of Toll-like receptor-1/2 combined with Velcade increases cytotoxicity to human multiple myeloma cells

原文发布日期：2013-05-31

DOI: 10.1038/bcj.2013.17

类型: Original Article

开放获取: 是

英文摘要：

An increasing body of evidence supports the important role of adhesion to bone marrow microenvironment components for survival and drug resistance of multiple myeloma (MM) cells. Previous studies suggested that stimulation of Toll-like receptors by endogenous ligands released during inflammation and tissue damage may be pro-tumorigenic, but no studies have been performed in relation to modulation of cell adhesion and drug cytotoxicity. Here, we investigated the effect of TLR1/2 activation on adhesion of human myeloma cells to fibronectin, and their sensitivity to the proteasome inhibitor Velcade. It was found that TLR1/2 activation with Pam3CSK4 increased the cytotoxicity of Velcade in L363, OPM-2 and U266 human myeloma cells. This effect was not related to a decreased adhesion of the cells to fibronectin, but TLR1/2 activation stimulated the caspase-3 activity in Velcade-treated myeloma cells, which may be responsible for the enhanced cell death. Inhibitors of NF-κB and MAPK reduced the stimulatory effect. These findings indicate that TLR activation of MM cells could bypass protective effects of cell adhesion and suggest that TLR signaling may also have antitumorigenic potential.

摘要翻译： 

越来越多的证据表明，骨髓微环境成分的粘附对多发性骨髓瘤（MM）细胞的存活和耐药性具有重要作用。先前的研究提示，在炎症和组织损伤过程中释放的内源性配体对Toll样受体的刺激可能具有促肿瘤发生作用，但尚未有研究涉及细胞粘附和药物细胞毒性的调节。本研究探讨了TLR1/2激活对人骨髓瘤细胞与纤维连接蛋白粘附的影响，以及它们对蛋白酶体抑制剂Velcade的敏感性。结果发现，使用Pam3CSK4激活TLR1/2可增强Velcade对L363、OPM-2和U266人骨髓瘤细胞的细胞毒性。这种效应与细胞对纤维连接蛋白粘附的减少无关，但TLR1/2激活刺激了Velcade处理的骨髓瘤细胞中caspase-3的活性，这可能是导致细胞死亡增强的原因。NF-κB和MAPK抑制剂可减弱这种刺激效应。这些发现表明，MM细胞的TLR激活可以绕过细胞粘附的保护作用，并提示TLR信号传导可能也具有抗肿瘤发生的潜力。

原文链接：

Stimulation of Toll-like receptor-1/2 combined with Velcade increases cytotoxicity to human multiple myeloma cells