Osthole inhibits GSK-3/AMPK/mTOR pathway-controlled glycolysis and increases radiosensitivity of subcutaneous transplanted hepatocellular carcinoma in nude mice

Purpose Osthole possesses anti-tumor activities. However, whether osthole can have a radiosensitization effect on hepatic cancer remains unclear. Here, an HCC-LM3 cells-inoculated subcutaneous transplanted tumor was adopted to explore the effect of osthole.Methods The tumor-bearing mice were treated with 100 mg/kg osthole for 12 days, 4 Gy irradiation twice, or their combination. The tumor volume and weight, lactic acid content, glycolytic enzyme activities, and protein expression of glycogen synthase kinase 3 beta (GSK-3 beta), p-GSK-3 beta, mammalian target of rapamycin (mTOR), p-mTOR, AMP-activated protein kinase (AMPK), p-AMPK, glucose transporter 1/3, and pyruvate kinase M2 were determined. The GSK-3 beta-overexpressed HCC-LM3 or SK-Hep-1 cell models were also adopted to verify the effects of osthole on expression of these proteins.Results The tumor volume and weight, lactic acid content, and glycolytic enzyme activities in tumor tissues were lower in the osthole + radiation group than in the radiation group. Moreover, osthole could reverse the radiation-induced increments of p-GSK-3 beta/GSK-3 beta and p-mTOR/mTOR protein ratios and the expression of glucose transporter 1/3 and pyruvate kinase M2 proteins in tumor tissues, and increase the protein ratio of p-AMPK/AMPK. The effects of osthole on these glycolysis-related proteins were also observed in GSK-3 beta-overexpressed HCC-LM3 or SK-Hep-1 cell models.Conclusion Osthole has a radiosensitizing effect on subcutaneous transplanted hepatocellular carcinoma, and its mechanism may be related to inhibition of GSK-3 beta/AMPK/mTOR pathway-controlled glycolysis.