Inhibition of the Wnt-β-catenin and Notch signaling pathways sensitizes osteosarcoma cells to chemotherapy

Abstract

Osteosarcoma (OS) is one of the most common malignant bone tumors in early adolescence. Multi-drug chemotherapy has greatly increased the five year survival rate from 20% to 70%. However, the rate has been staggering for 30 years and the prognosis is particularly poor for patients with recurrence and metastasis. Our study aimed to investigate the role of Wnt-β-catenin, Notch and Hedgehog pathway in OS development because all these pathways are involved in skeletal development, tumorigenesis and chemoresistance. Our results showed that the major components in Wnt-β-catenin pathway, e.g. Wnt3a, β-catenin and Lef1, were consistently upregulated in human osteosarcoma cell line Saos2 cells compared to human fetal osteoblasts (hFOB), whereas the changes in the expression levels of Notch and Hh signaling molecules were not consistent. Knocking down β-catenin increased the Saos2 sensitivity to methotrexate (MTX) induced cell death. Consistently, the expression level of β-catenin protein correlated with the invasiveness of OS, as evidenced by more intensive β-catenin immunoreactivity in higher grade OS samples. Chemical inhibition of the Wnt-β-catenin signaling enhanced MTX mediated death of Saos2 cells. A synergistic effect with MTX was observed when both inhibitors for Wnt-β-catenin and Notch pathways were simultaneously used, while the addition of the Hh inhibitor did not further improve the efficacy. Our findings provide some novel insight to OS pathogenesis and lay a foundation for future application of Wnt-β-catenin and Notch inhibitors together with the currently used chemotherapeutic drugs to improve the outcome of OS treatment.

Whole exome sequencing of a single osteosarcoma case¿integrative analysis with whole transcriptome RNA-seq data

“…Additionally, genes with CD-SNVs-RARA, SMO and SOX7 were upregulated [10]. Thus, our results are rather controversial to several previous studies demonstrating the WNT/β-catenin pathway to be upregulated [47][48][49]. However, there are also studies correlating to our findings [50,51].…”

miR-34a is downregulated in human osteosarcoma stem-like cells and promotes invasion, tumorigenic ability and self-renewal capacity

“…Despite the combination of chemotherapeutics and aggressive surgery, there have been no significant improvements in the long-term survival rates of patients due to the presence of metastases at initial diagnosis and of chemoresistance (2). Several factors lead to chemoresistance, including activation of the Wnt-β-catenin pathway or upregulated microRNAs (miRNAs), which target apoptotic factors (3,4). In addition, increasing evidence has supported the hypothesis that a small cell sub-culture presenting with stem-like properties is responsible for cancer relapse (5), which suggests the existence of osteosarcoma stem-like cells (OSCs).…”

Icaritin suppresses the proliferation of human osteosarcoma cells in vitro by increasing apoptosis and decreasing MMP expression

“…Osteosarcoma (OS) is one of the most common malignant bone tumors during childhood and adolescence and is the second leading cause of mortality in this age group [10,11] . This type of bone tumor is characterized by a highly malignant and metastatic potential, and approximately 80% of osteosarcomas originate in the appendicular skeleton.…”