Abstract
Osteosarcoma is a highly common malignant bone tumor. Its highly metastatic properties are the leading cause of mortality for cancer. Niclosamide, a salicylanilide derivative, is an oral antihelminthic drug of known anticancer potential. However, the effect of niclosamide on osteosarcoma cell migration, invasion and the mechanisms underlying have not been fully clarified. Therefore, this study investigated niclosamide’s underlying pathways and antimetastatic effects on osteosarcoma. In this study, U2OS and HOS osteosarcoma cell lines were treated with niclosamide and then subjected to assays for determining cell migration ability. The results indicated that niclosamide, at concentrations of up to 200 nM, inhibited the migration and invasion of human osteosarcoma U2OS and HOS cells and repressed the transforming growth factor beta-induced protein (TGFBI) expression of U2OS cells, without cytotoxicity. After TGFBI knockdown occurred, cellular migration and invasion behaviors of U2OS cells were significantly reduced. Moreover, niclosamide significantly decreased the phosphorylation of ERK1/2 in U2OS cells and the combination treatment of the MEK inhibitor (U0126) and niclosamide resulted in the intensive inhibition of the TGFBI expression and the migratory ability in U2OS cells. Therefore, TGFBI derived from osteosarcoma cells via the ERK pathway contributed to cellular migration and invasion and niclosamide inhibited these processes. These findings indicate that niclosamide may be a powerful preventive agent against the development and metastasis of osteosarcoma.
Highlights
After U2OS cells were treated for 24 h and 48 h and HOS cells for 12 h and 24 h, niclosamide significantly reduced the motility of U2OS and HOS cells in the wound healing assay (Figure 2A)
We revealed that niclosamide can effectively inhibit the cell migration and invasion of osteosarcoma cell lines by reducing the expression of transforming growth factor beta-induced protein (TGFBI)
The antimetastatic activity of niclosamide is associated with inhibitory effects on several signaling pathways, such as the STAT3 pathway in melanoma, [24] in oral squamous cell carcinoma, [25] and in prostate cancer [26]; Wnt/β-catenin signaling in oral squamous cell carcinoma [27] and in adrenocortical carcinoma [28]; Notch signaling in colon cancer [29]; and IGF signaling in ovarian cancer [30]
Summary
Osteosarcoma is a highly common type of malignant orthotopic bone tumor and mainly occurs in children and young adults. Current comprehensive treatments for patients with osteosarcoma typically include chemotherapy before and after surgery in combination with the surgical removal of the tumor [3]. The survival rate of patients with localized osteosarcoma has improved in recent years with advances in therapeutic approaches [4]. Due to the strong invasiveness of osteosarcoma and its rapid progression, the prognosis for patients with metastatic osteosarcoma remains unfavorable [5,6]. Tumor metastasis and relapse remain the leading causes of mortality for patients with osteosarcoma [7,8]. Identifying effective drugs for the treatment of osteosarcoma is crucial
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