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Deregulation of aerobic glycolysis is a common phenomenon in human cancers, including glioblastoma (GBM). In the present study, we demonstrated that the natural compound xanthohumol has a profound anti-tumor effect on GBM via direct inhibition of glycolysis. Xanthohumol suppressed cell proliferation and colony formation of GBM cells, and significantly impaired glucose metabolism via inhibiting Hexokinase 2 (HK2) expression. We demonstrated that down-regulation of c-Myc was required for xanthohumol-induced decrease of HK2. Xanthohumol destabilization of c-Myc, and promoted FBW7-mediated ubiquitination of c-Myc. Xanthohumol attenuated Akt activity and inhibited the activation of GSK3β, resulted in c-Myc degradation. Overexpression of Myr-Akt1 significantly rescued xanthohumol-mediated c-Myc inhibition and glycolysis suppression. Finally, the xanthohumol-mediated down-regulation of the PI3-K/Akt-GSK3beta-FBW7 signaling axis promoted the destabilization of c-Myc. Finally, the animal results demonstrated that xanthohumol substantially inhibited tumor growth in vivo . Collectively, xanthohumol appears to be a promising new anti-tumor agent with the therapeutic potential for GBM.

Xanthohumol suppresses glioblastoma via modulation of Hexokinase 2 -mediated glycolysis