Niclosamide Suppresses Migration and Invasion of Human Osteosarcoma Cells by Repressing TGFBI Expression via the ERK Signaling Pathway

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.

Identification of Factors Driving Doxorubicin-Resistant Ewing Tumor Cells to Survival

“…Using the analysis approach, we identified several proteins with differential expression between M19 and ES36. All these proteins are of particular interest since their roles in promoting metastases [ 25 , 26 ] and sarcoma progression [ 27 , 28 ] have been demonstrated.…”

Niclosamide is a potential candidate for the treatment of chemo-resistant osteosarcoma

“…Niclosamide is an attractive candidate as it is already available for clinical use to treat parasitic infections in millions of people worldwide. It has been shown to be active in osteosarcoma cell lines, U2OS, HOS and MG63, and, furthermore, to prevent metastatic spread in the lungs in a mouse model of osteosarcoma ( Li et al, 2015 ; Reddy et al, 2020 ; Yeh et al, 2022 ). The effect of niclosamide on osteosarcoma cells resistant to chemotherapy, a most relevant issue, had not yet been investigated.…”

“…Wnt/β-catenin, ATF3, PERK, eIF4E, NK-ĸB, STAT3, and mTOR have been reported to be involved in niclosamide’s action in cancer cells ( Arend et al , 2016 ; Liu Z et al, 2016 ; Weng et al, 2016 ; Wang et al , 2019 ; Wei et al , 2021 ). Several studies also highlight the inhibitory effects of niclosamide on osteosarcoma cells and xenograft mouse model ( Li et al , 2015 ; Reddy et al, 2020 ; Yi et al, 2021 ; Yeh et al, 2022 ). However, it is not known whether niclosamide is effective against chemo-resistant osteosarcoma.…”

Disturbance of the Warburg effect by dichloroacetate and niclosamide suppresses the growth of different sub-types of malignant pleural mesothelioma in vitro and in vivo

“…It has been demonstrated that DCA inhibits migration ( Florio et al, 2018 ; Tataranni et al, 2019 ; Guo et al, 2022a ) of cells as well as invasion ( Guo et al, 2022a ). Nic has been shown to have anti-migratory and anti-invasive properties ( Zhu et al, 2019 ; Guo et al, 2022b ; Yeh et al, 2022 ). In this study, DCA inhibited migration in H226 cells while Nic suppressed migration in 3 MPM cells lines.…”