Gambogic acid inhibits multiple myeloma mediated osteoclastogenesis through suppression of chemokine receptor CXCR4 signaling pathways
Gambogic acid inhibits multiple myeloma mediated osteoclastogenesis through suppression of chemokine receptor CXCR4 signaling pathways
复制标题
DOI：
10.1016/j.exphem.2014.07.261
复制
发表时间：
2014-10-01
影响因子：
2.6
通讯作者：
Amin, Shantu G.
中科院分区：
文献类型：
--
作者：
Pandey, Manoj K.;Kale, Vijay P.;Amin, Shantu G.
多发性骨髓瘤（MM）的标志是以存在溶解性病变和骨质疏松为特征的骨疾病。基质细胞衍生因子1 α（SDF-1 α）及其受体CXC趋化因子受体4（CXCR 4）被认为是骨吸收的调节因子，这表明可以抑制SDF 1 α/CXCR 4信号传导的药物可能会抑制破骨细胞生成，这是一个与骨吸收密切相关的过程。因此，我们研究了藤黄酸（GA），一种氧杂蒽酮，是否可以抑制CXCR 4信号传导和抑制MM细胞诱导的破骨细胞生成。通过对接研究，我们预测GA直接与CXCR 4相互作用。这种氧杂蒽酮以剂量和时间依赖性方式下调MM细胞上CXCR 4的表达。CXCR 4的下调不是由于蛋白水解降解，而是GA通过抑制核因子-κ B（NF-κ B）DNA结合来抑制CXCR 4 mRNA表达。这通过定量染色质免疫沉淀测定进一步证实，因为GA抑制CXCR 4启动子处的p65结合。GA通过抑制MM细胞中Akt、p38和Erk 1/2的磷酸化，抑制SDF-1 α诱导的MM细胞趋化性和CXCR 4下游信号传导。GA以剂量和时间依赖性方式消除了RANKL诱导的巨噬细胞向破骨细胞的分化。此外，我们发现MM细胞诱导巨噬细胞分化为破骨细胞，GA抑制这一过程。重要的是，GA对破骨细胞生成的抑制是通过IL-6抑制介导的。总之，我们的研究结果表明，GA是一种新的CXCR 4表达抑制剂，并具有很强的潜力，抑制破骨细胞介导的MM细胞。爱思唯尔公司出版代表ISEH -国际实验血液学学会。
Bone disease, characterized by the presence of lytic lesions and osteoporosis is the hallmark of multiple myeloma (MM). Stromal cell-derived factor 1 alpha (SDF-1 alpha) and its receptor, CXC chemokine receptor 4 (CXCR4), has been implicated as a regulator of bone resorption, suggesting that agents that can suppress SDF1 alpha/CXCR4 signaling might inhibit osteoclastogenesis, a process closely linked to bone resorption. We, therefore, investigated whether gambogic acid (GA), a xanthone, could inhibit CXCR4 signaling and suppress osteoclastogenesis induced by MM cells. Through docking studies we predicted that GA directly interacts with CXCR4. This xanthone down-regulates the expression of CXCR4 on MM cells in a dose- and time-dependent manner. The down-regulation of CXCR4 was not due to proteolytic degradation, but rather GA suppresses CXCR4 mRNA expression by inhibiting nuclear factor-kappa B (NF-kappa B) DNA binding. This was further confirmed by quantitative chromatin immunoprecipitation assay, as GA inhibits p65 binding at the CXCR4 promoter. GA suppressed SDF-1 alpha-induced chemotaxis of MM cells and downstream signaling of CXCR4 by inhibiting phosphorylation of Akt, p38, and Erk1/2 in MM cells. GA abrogated the RANKL-induced differentiation of macrophages to osteoclasts in a dose- and time-dependent manner. In addition, we found that MM cells induced differentiation of macrophages to osteoclasts, and that GA suppressed this process. Importantly, suppression of osteoclastogenesis by GA was mediated through IL-6 inhibition. Overall, our results show that GA is a novel inhibitor of CXCR4 expression and has a strong potential to suppress osteoclastogenesis mediated by MM cells. Published by Elsevier Inc. On behalf of ISEH - International Society for Experimental Hematology.