Notch signaling is important for epithelial-mesenchymal transition induced by low concentrations of doxorubicin in osteosarcoma cell lines

Abstract

Osteosarcoma is an aggressive pediatric tumor affecting growing bones that typically occurs in adolescents and young adults. Although advances in treatment have been made in recent years, a high proportion of patients relapse due to metastases, which are frequently resistant to chemotherapy and pose a significant threat to long-term survival. Previous studies have demonstrated that the epithelial-mesenchymal transition (EMT) is associated with cancer occurrence and metastasis, and our previous study demonstrated the occurrence of EMT in osteosarcoma. Notch is a regulator involved in several cellular processes, and previous studies have identified that the Notch signaling pathway may be activated during chemotherapy. However, whether chemotherapy affects the EMT remains to be elucidated. To address this issue, in the present study osteosarcoma cells were exposed to sublethal doses of doxorubicin, which resulted in upregulation of the expression of genes in the Notch signaling pathway and its target genes. Furthermore, doxorubicin treatment promoted mesenchymal-like properties and enhanced the migration and invasion of cells. In addition, treatment with the selective γ-secretase inhibitor DAPT was able to prevent the EMT and inhibit the in vitro migration of osteosarcoma cells. The results of this study suggested that there is a significant correlation between the Notch signaling pathway and the EMT, and revealed an underlying molecular mechanism by which doxorubicin may induce the EMT via Notch signaling.

miR-184 Inhibits Tumor Invasion, Migration and Metastasis in Nasopharyngeal Carcinoma by Targeting Notch2

“…This progression can be triggered by various developmental signalling pathways, such as tumour growth factor beta, Wnt, Notch, growth factor receptor tyrosine kinases and PLC-γ pathways [25]. Notch signalling is an evolutionarily conserved pathway involved in EMT and metastasis [29][30][31][32][33]. In mammals, Notch signalling includes four transmembrane Notch receptors (Notch-1, Notch-2, Notch-3 and Notch-4) and five canonical transmembrane ligands (Delta-like DLL1,DLL3, DLL4, Jagged-1 and Jagged-2) [34].…”

β‑carotene reverses tobacco smoke‑induced gastric EMT via Notch pathway in vivo

“…Nonetheless, the underlying mechanisms by which tobacco smoke induces EMT and the signaling events that underlie EMT are poorly understood. Notch signaling regulates a series of cellular processes (21). Several studies have revealed that Notch pathway is critically involved in the process of EMT (21,23,24).…”

“…Notch signaling regulates a series of cellular processes (21). Several studies have revealed that Notch pathway is critically involved in the process of EMT (21,23,24). To examine the role of Notch pathway in tobacco smoke-induced EMT, we addressed the relationship between Notch and gastric EMT induced by tobacco smoke.…”

“…Notch signaling regulates a series of cellular processes (21). In addition, the Notch pathway has been reported implicated in a majority of cancers for promoting the malignant phenotype by inducing cell proliferation, drug resistance, resistance to apoptosis, invasion and metastasis (22).…”

“…In addition, the Notch pathway has been reported implicated in a majority of cancers for promoting the malignant phenotype by inducing cell proliferation, drug resistance, resistance to apoptosis, invasion and metastasis (22). Several studies have revealed that Notch pathway is critically involved in the process of EMT (21,23,24). Nonetheless, no studies have been done to examine the role of Notch pathway in tobacco smoke-induced gastric EMT.…”