CXCR3 confers sorafenib resistance of HCC cells through regulating metabolic alteration and AMPK pathway

Currently, the acquired resistance of the hepatocellular carcinoma (HCC) first-line therapeutic agent-sorafenib (SOR) remains a major challenge for HCC management. Recent evidence suggested the association between CXCL/CXCRs chemokines and chemotherapy resistant in Cancer cells. Hence, exploring the internal mechanism of CXCRs involved in SOR resistance will help to improve the efficacy of HCC. SOR-resistant HCC cells (Huh7-SOR) were established through escalating concentration of SOR. Glucose consumption, lactate production, intracellular ATP levels and oxygen consumption of HCC cells were determined by using the associated detected kits. Effects of CXCR3 on metabolic phenotype of HCC cells, AMPK pathway activity and adipocytokines were demonstrated by knocking down CXCR3 expression with the CXCR3 siRNA technique combined with qPCR and western blot. During the indicated procedure, SOR-resistant HCC cells-Huh7-SOR presented EMT-like morphologic change and underwent glycolysis to OXPHOS switch, representing reduced glucose consumption and lactate production, but increased oxygen consumption level and intercellular ATP levels. Moreover, metabolic alteration in SOR-resistance HCC cells was mediated by CXCR3. Mechanistically, CXCR3 induced metabolic alteration in SOR-resistance HCC cells through downregulating AMPK pathway activity and lipid peroxidation as well as upregulating levels of adipocytokines. The activation of A MPK pathway with metformin achieved the sensitization of HCC to SOR treatment in vivo. These findings unravel the association between metabolic alteration and SOR-resistance in HCC cells and demonstrate an important role of CXCR3 in the development of HCC cells resistance to SOR treatment and a novel mechanism of CXCR3 regulating AMPK pathway activity and adipocytokine signaling, lipid peroxidation resulted in metabolic alteration during the chemoresistance.