J Cancer 2020; 11(14):4047-4058. doi:10.7150/jca.33045
Xanthohumol suppresses glioblastoma via modulation of Hexokinase 2 -mediated glycolysis
1. Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China.
2. The Institute of Skull Base Surgery and Neuro-oncology at Hunan, 87 Xiangya Road, Changsha, Hunan, 410008, China.
Yuan J, Peng G, Xiao G, Yang Z, Huang J, Liu Q, Yang Z, Liu D. Xanthohumol suppresses glioblastoma via modulation of Hexokinase 2 -mediated glycolysis. J Cancer 2020; 11(14):4047-4058. doi:10.7150/jca.33045. Available from http://www.jcancer.org/v11p4047.htm
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.
Keywords: glioblastoma, xanthohumol, Hexokinases II, c-Myc, glycolysis