Apatinib ameliorates doxorubicin-induced migration and cancer stemness of osteosarcoma cells by inhibiting Sox2 via STAT3 signalling

BACKGROUND: Osteosarcoma, ranking as the second primary cause of cancer-related death, is the most common type of bone cancer. Doxorubicin (DOX) is used as a first-line treatment for osteosarcoma; however, the tumour recurrence rate remains high. Recent studies have suggested that DOX-induced migration and stemness in osteosarcoma cells might be the primary reason of recurrence and drug resistance. However, the underlying mechanisms remain unclear. Therefore, it is urgent to explore novel effective treatments to overcome DOX-induced drug resistance of osteosarcoma. METHODS: Osteosarcoma cells KHOS and U2OS were treated with DOX and apatinib (AP) alone or in combination. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays were performed to evaluate effects on proliferation. Flow cytometry analysis was carried out to assess cell apoptosis. Cell migration was determined by the transwell assay. Cancer stemness was detected by flow cytometry analysis of CD133(+) cells and sphere-formation assay. Western blot assay was used to measure the expression of E-cadherin, N-cadherin, vimentin, matrix metalloproteinase 9 (MMP-9), signal transducer and activator of transcription 3 (STAT3)/p-STAT3, SRY-box2 (Sox2) and octamer-binding protein 4 (Oct4), and Nanog in treated osteosarcoma cells. RESULTS: Herein, we revealed that AP treatment significantly enhanced the sensitivity of osteosarcoma cells to DOX, reversed the DOX-induced stemness phenotype and metastasis capacity of osteosarcoma cells, and abolished the upregulation of p-STAT3, Sox2, Oct4, and Nanog. We further demonstrated that AP reversed DOX-induced stemness and migration of osteosarcoma cells through Sox2. CONCLUSION: These results suggested that AP significantly abolished the DOX-induced stemness phenotype and metastasis capacity in osteosarcoma cells by inhibiting Sox2 via STAT3 signalling. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Our study indicates that Doxorubicin-based chemotherapeutics may simulate cancer stem cells (CSCs) properties in osteosarcoma, leading to the resistance of osteosarcoma. Apatinib can reduce the Doxorubicin-induced chemoresistance through STAT3/Sox2 pathway inactivation. This study represents that Apatinib may act as an effective chemotherapy sensitiser for reducing chemoresistance correlated with CSCs in osteosarcoma.