Objective: This study aimed to investigate the regulatory effect of ivermectin (IVM) on energy metabolism in glioma progression, and provide a reference for the treatment of glioma.
Methods: Glioma cells were treated with IVM to measure cell viability, autophagy marker protein expression, ATP content, glucose uptake, pyruvate content, and expression of key enzymes of glycolysis. Glucose transporter 4 (GLUT4) or siGLUT4 was transfected in IVM treated U87 cells to investigate the effect of GLUT4 on cellular glycolysis and autophagy. The JAK2 inhibitor AZD-1480 was introduced to explore the specific mechanism by which IVM regulates glycolysis and autophagy. Rat models of glioma xenograft were constructed and treated with 10 mg/kg IVM to observe tumor growth and examine the expression levels of GLUT4 and autophagy marker proteins in tumor tissues.
Results: IVM inhibited glioma cell survival and promoted cell death. IVM promoted LC3-II protein expression and inhibited p62/SQSTM1 protein expression in glioma cells. IVM decreased adenosine-triphosphate (ATP) and pyruvate content, promoted glucose uptake, and reduced HK2 and PFK1 protein expression in U87 cells. IVM inhibited GLUT4 protein expression, and overexpression of GLUT4 promoted glycolysis and inhibited autophagic cell death in U87 cells. IVM inhibited glycolysis by blocking GLUT4 mediated the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway activation. IVM inhibited tumor growth in vivo, decreased the protein expression of GLUT4, JAK2, HK2, and PFK1 in tumor tissues, decreased the phosphorylation levels of STAT3/STAT5, and promoted the expression of autophagy marker proteins.
Conclusions: IVM accelerates autophagic death of glioma cells by inhibiting glycolysis through blocking GLUT4 mediated JAK/STAT signaling pathway activation.
Keywords: GLUT4; autophagy; glioma; glycolysis; ivermectin; the JAK/STAT signaling pathway.
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