Melittin inhibits tumor angiogenesis modulated by endothelial progenitor cells associated with the SDF-1α/CXCR4 signaling pathway in a UMR-106 osteosarcoma xenograft mouse model.
Melittin inhibits tumor angiogenesis modulated by endothelial progenitor cells associated with the SDF-1α/CXCR4 signaling pathway in a UMR-106 osteosarcoma xenograft mouse model.
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DOI：
10.3892/mmr.2016.5215
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发表时间：
2016-07
影响因子：
3.4
通讯作者：
Ye Y
中科院分区：
文献类型：
--
作者：
Qin G;Chen Y;Li H;Xu S;Li Y;Sun J;Rao W;Chen C;Du M;He K;Ye Y
内皮祖细胞（EPCs）在肿瘤血管生成中起重要作用。基质细胞衍生因子-1 α（SDF-1α）及其受体C-X-C趋化因子受体4（CXCR 4）是干细胞归巢的关键。蜂毒肽是蜂毒中的一种成分，具有抗肿瘤活性，但其作用机制尚不清楚。本研究旨在评估蜂毒素对骨肉瘤小鼠模型中EPCs和血管生成的影响。用不同浓度的蜂毒素处理UMR-106细胞和EPCs，并使用MTT测定法测定细胞活力。观察内皮祖细胞的粘附、迁移和成管能力。Western blotting检测SDF-1α、AKT和细胞外信号调节激酶（ERK）1/2的表达。裸小鼠接种UMR-106细胞建立骨肉瘤模型。肿瘤注射蜂毒素，并通过免疫组织化学和免疫荧光法评估其效果。蜂毒肽降低UMR-106细胞和EPCs的活力。此外，与对照和SDF-1α处理的细胞相比，它降低了EPC粘附、迁移和管形成。与对照组相比，蜂毒肽可降低UMR-106细胞和EPCs中磷酸化（p）-AKT、p-ERK 1/2、SDF-1α和CXCR 4的表达。对照组CD 34/CD 133双阳性细胞比例为16.4±10.4%，而160、320和640 μg/kg蜂毒素组分别为7.0±4.4、2.9±1.2和1.3±0.3%（P<0.05）。在第11天，与对照组相比，蜂毒素减小了肿瘤大小（对照组，4.8±1.3 cm 3; 160、320和640 µg/kg蜂毒素分别为3.2±0.6、2.6±0.5和2.0±0.2 cm 3;所有P<0.05）。蜂毒肽可降低肿瘤微血管密度、SDF-1α和CXCR 4蛋白表达水平。蜂毒肽可能通过抑制SDF-1α/CXCR 4信号通路降低骨肉瘤对EPC介导的血管生成的影响。
Endothelial progenitor cells (EPCs) are important in tumor angiogenesis. Stromal cell-derived factor-1α (SDF-1α) and its receptor C-X-C chemokine receptor type 4 (CXCR4) are key in stem cell homing. Melittin, a component of bee venom, exerts antitumor activity, however, the underlying mechanisms remain to be elucidated. The present study aimed to assess the effects of melittin on EPCs and angiogenesis in a mouse model of osteosarcoma. UMR-106 cells and EPCs were treated with various concentrations of melittin and cell viability was determined using the MTT assay. EPC adherence, migration and tube forming ability were assessed. Furthermore, SDF-1α, AKT and extracellular signal-regulated kinase (ERK)1/2 expression levels were detected by western blotting. Nude mice were inoculated with UMR-106 cells to establish an osteosarcoma mouse model. The tumors were injected with melittin, and its effects were assessed by immunohistochemistry and immunofluorescence. Melittin decreased the viability of UMR-106 cells and EPCs. In addition, it decreased EPC adhesion, migration and tube formation when compared with control and SDF-1α-treated cells. Melittin decreased the expression of phosphorylated (p)-AKT, p-ERK1/2, SDF-1α and CXCR4 in UMR-106 cells and EPCs when compared with the control. The proportions of cluster of differentiation (CD)34/CD133 double-positive cells were 16.4±10.4% in the control, and 7.0±4.4, 2.9±1.2 and 1.3±0.3% in tumors treated with 160, 320 and 640 µg/kg melittin per day, respectively (P<0.05). At 11 days, melittin reduced the tumor size when compared with that of the control (control, 4.8±1.3 cm3; melittin, 3.2±0.6, 2.6±0.5, and 2.0±0.2 cm3 for 160, 320 and 640 µg/kg, respectively; all P<0.05). Melittin decreased the microvessel density, and SDF-1α and CXCR4 protein expression levels in the tumors. Melittin may decrease the effect of osteosarcoma on EPC-mediated angiogenesis, possibly via inhibition of the SDF-1α/CXCR4 signaling pathway.