Arsenic trioxide inhibits Ewing’s sarcoma cell invasiveness by targeting p38MAPK and c-Jun N-terminal kinase

Abstract

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 p38(MAPK) (sb202190) and c-Jun NH₂-terminal kinase (JNK, sp600125) were used in invasion assays to determine the effect of p38(MAPK) 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-p38(MAPK), and phosphor-JNK were suppressed by As₂O₃ treatment in a dose-dependent manner. The inhibitors of p38(MAPK) (sb202190) and JNK (sp600125) enhanced the inhibition induced by As₂O₃, which was counteracted by anisomycin, an activating agent of p38(MAPK) 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.

Arsenic trioxide-induced cytotoxicity in small cell lung cancer via altered redox homeostasis and mitochondrial integrity

“…MAPKs are potential ROS response factors, nonetheless, p-JNK and p-p38 were not involved in ATO-induced cell death in our H841 cell line model (data not shown), which is different from other cancer models (69)(70)(71). Although upregulated p-Erk1/2 was detected after ATO treatment in H841 cells, specific Erk inhibitor PD98059 failed to revert the effects induced by ATO on MMD and cell death.…”

Identifications of genetic differences between metastatic and non-metastatic osteosarcoma samples based on bioinformatics analysis

“…Comparing to normal sample, OS and metastatic OS showed higher activity in cell cycle, cell differentiation, tumor metastasis, and MYC pathway. Moreover, metastatic OS owed higher MAPK signaling pathway activity than non-metastatic OS, supporting the viewpoint that MAPK signaling pathway abnormality is highly correlated to Ewing's sarcoma invasion [24], the potential main factor for metastasis.…”

MicroRNAs in Invasion and Metastasis in Lung Cancer

“…The presence of at least six MAPK in yeast suggests that there are more in mammals: extracellular signal-regulated kinases (ERK1, ERK2), c-Jun N-terminal kinases (JNKs), p38 isoforms, ERK5, ERK3/4, ERK7/8. In vivo and in vitro studies have confirmed that three major subgroups of MAPK including ERK1/2, JNK, and p38, are specifically involved in invasion and metastasis [9,10,62].…”

“…Cellular migration and invasion mechanism are commonly thought to be associated with Rho family GTPases [2][3][4], JAK-STAT [5][6][7], MAPK [8][9][10], Wnt [11][12][13], Notch pathway [14][15][16]. Recently, epithelial-mesenchymal transition (EMT) programs have become the focus of the mechanism of metastasis [1,[17][18][19][20].…”