Chemotherapy-driven increases in the IL6/STAT3/Mcl-1 axis reduce the chemosensitivity of osteosarcoma cells

Abstract Osteosarcoma (OS) remains one of the most uncontrollable and devastating malignant tumors and is very prone to chemotherapy resistance as the main reason for treatment failure. Previous study found that chemotherapy itself can stimulate Mcl-1 upregulation in OS cells, which in turn inhibits the chemosensitivity of OS cells, but the basic process by which this occurs is unknown. The present study found that chemotherapy upregulated the expression of Mcl-1, which led to a decrease in the chemosensitivity of tumors by promoting their proliferation, invasion, and metastasis. The IL6/STAT3 axis was the critical regulator of Mcl-1 expression in OS cells receiving chemotherapy. Mechanistic analysis suggested that enhanced the DNA damage repair machinery was the mechanism by which chemotherapy-driven increases in the IL6/STAT3/Mcl-1 axis led to chemoresistance. Therefore, chemotherapy-driven increases in the IL6/STAT3/Mcl-1 axis are the key in chemoresistance, suggesting the potential for a novel strategy to enhance chemosensitivity in OS.