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Xanthohumol suppresses glioblastoma via modulation of Hexokinase 2 -mediated glycolysis
Jian Yuan1,2, Gang Peng1,2, Gelei Xiao1
1Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China.
Abstract:
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.
Insights
Xanthohumol, a natural compound, effectively inhibits glioblastoma (GBM) growth by targeting glycolysis and c-Myc. This compound shows promise as a novel anti-cancer agent for GBM treatment.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Deregulation of aerobic glycolysis is a hallmark of human cancers, including glioblastoma (GBM).
- Targeting cancer-specific metabolic pathways offers a potential therapeutic strategy.
Purpose of the Study:
- To investigate the anti-tumor effects of xanthohumol on glioblastoma.
- To elucidate the molecular mechanisms underlying xanthohumol's action, focusing on glycolysis and c-Myc regulation.
Main Methods:
- Assessed xanthohumol's impact on GBM cell proliferation, colony formation, and glucose metabolism.
- Investigated the role of Hexokinase 2 (HK2) and c-Myc in xanthohumol's anti-tumor effects.
- Analyzed the PI3-K/Akt-GSK3beta-FBW7 signaling pathway and c-Myc ubiquitination.
- Evaluated xanthohumol's efficacy in an *in vivo* GBM tumor model.
Main Results:
- Xanthohumol suppressed GBM cell proliferation and colony formation.
- It inhibited glucose metabolism by down-regulating Hexokinase 2 (HK2) expression.
- Xanthohumol destabilized c-Myc via FBW7-mediated ubiquitination, involving the Akt-GSK3β pathway.
- *In vivo* studies showed significant inhibition of tumor growth.
Conclusions:
- Xanthohumol exhibits potent anti-tumor activity against glioblastoma by inhibiting glycolysis through c-Myc destabilization.
- The PI3-K/Akt-GSK3beta-FBW7 signaling axis is crucial for xanthohumol's effects.
- Xanthohumol represents a promising therapeutic candidate for GBM treatment.
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