Arsenic trioxide inhibits Ewing’s sarcoma cell invasiveness by targeting p38MAPK and c-Jun N-terminal kinase
Arsenic trioxide inhibits Ewing’s sarcoma cell invasiveness by targeting p38MAPK and c-Jun N-terminal kinase
复制标题
DOI：
10.1097/cad.0b013e32834bfd68
复制
发表时间：
2012-01
影响因子：
2.3
通讯作者：
Shuai Zhang;W. Guo;T. Ren;Xin Lu;Guo-Qing Tang;Fu-long Zhao
中科院分区：
文献类型：
--
作者：
Shuai Zhang;W. Guo;T. Ren;Xin Lu;Guo-Qing Tang;Fu-long Zhao
尤文氏肉瘤是第二常见的原发性恶性骨肿瘤，主要影响儿童和年轻人。这种肿瘤臭名昭著的转移能力提高了患者的死亡率，仍然是一个有待克服的问题。我们研究了三氧化二砷（As 2 O3）对尤文肉瘤细胞转移能力的影响。我们进行了3-（4，5-二甲基噻唑-2-基）-2，5-二苯基-2H-溴化四唑测定，以选择合适的As 2 O3浓度进行实验。迁移，侵袭和粘附实验进行评估的影响，As 2 O3尤文肉瘤的转移。免疫荧光染色观察了As 2 O3处理后尤文肉瘤细胞骨架的重组。用蛋白质印迹法检测基质金属蛋白酶-9表达和丝裂原活化蛋白激酶（MAPK）通路的变化。p38 MAPK（sb 202190）和c-Jun NH 2-末端激酶（JNK，sp 600125）的抑制剂用于侵袭测定以确定p38 MAPK和JNK的作用。我们发现，As 2 O3可以显着抑制尤文肉瘤细胞的迁移和侵袭能力与肌动蛋白细胞骨架的结构重排。As 2 O3处理可抑制基质金属蛋白酶-9、磷酸化p38 MAPK和磷酸化JNK的表达，且呈剂量依赖性。p38 MAPK（sb 202190）和JNK（sp 600125）的抑制剂可增强As 2 O3的抑制作用，而p38 MAPK和JNK的激活剂茴香霉素可拮抗As 2 O3的抑制作用。本研究结果表明，As_2O_3能抑制RD-ES和A-673细胞的转移能力，可能对尤文肉瘤有新的治疗价值。
Ewing’s sarcoma is the second most frequent primary malignant bone tumor, mainly affecting children and young adults. The notorious metastatic capability of this tumor aggravates patient mortality and remains a problem to be overcome. We investigated the effect of arsenic trioxide (As2O3) on the metastasis capability of Ewing’s sarcoma cells. We performed 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazolium bromide assays to choose appropriate concentrations of As2O3 for the experiments. Migration, invasion, and adhesion assays were performed to assess the effect of As2O3 on the metastasis of Ewing’s sarcoma. Immunofluorescent staining was used to observe cytoskeleton reorganization in Ewing’s sarcoma cells treated with As2O3. Changes in matrix metalloproteinase-9 expression and the mitogen-activated protein kinase (MAPK) pathway were investigated using western blot. Inhibitors of p38MAPK (sb202190) and c-Jun NH2-terminal kinase (JNK, sp600125) were used in invasion assays to determine the effect of p38MAPK and JNK. We found that As2O3 may markedly inhibit the migration and invasion capacity of Ewing’s sarcoma cells with structural rearrangements of the actin cytoskeleton. The expressions of matrix metalloproteinase-9, phosphor-p38MAPK, and phosphor-JNK were suppressed by As2O3 treatment in a dose-dependent manner. The inhibitors of p38MAPK (sb202190) and JNK (sp600125) enhanced the inhibition induced by As2O3, which was counteracted by anisomycin, an activating agent of p38MAPK and JNK. Taken together, our results demonstrate that As2O3 can inhibit the metastasis capability of RD-ES and A-673 cells and may have new therapeutic value for Ewing’s sarcoma.