2‐Deoxy‐d‐glucose Simultaneously Targets Glycolysis and Wnt/β‐catenin Signaling to Inhibit Cervical Cancer Progression

Cervical cancer is one of the most common female malignant tumors, with typical cancer metabolism characteristics of increased glycolysis flux and lactate accumulation. 2-Deoxy-D-glucose (2-DG) is a glycolysis inhibitor that acts on hexokinase, the first rate-limiting enzyme in the glycolysis pathway. In this research, we demonstrated that 2-DG effectively reduced glycolysis and impaired mitochondrial function in cervical cancer cell lines HeLa and SiHa. Cell function experiments revealed that 2-DG significantly inhibited cell growth, migration, and invasion, and induced G0/G1 phase arrest at non-cytotoxic concentrations. In addition, we found that 2-DG down-regulated Wingless-type (Wnt)/β-catenin signaling. Mechanistically, 2-DG accelerated the degradation of β-catenin protein, which resulted in the decrease of β-catenin expression in both nucleus and cytoplasm. The Wnt agonist lithium chloride and β-catenin overexpression vector could partially reverse the inhibition of malignant phenotype by 2-DG. These data suggested that 2-DG exerted its anti-cancer effects on cervical cancer by co-targeting glycolysis and Wnt/β-catenin signaling. As expected, the combination of 2-DG and Wnt inhibitor synergistically inhibited cell growth. It is noteworthy that, down-regulation of Wnt/β-catenin signaling also inhibited glycolysis, indicating a similar positive feedback regulation between glycolysis and Wnt/β-catenin signaling. In conclusion, we investigated the molecular mechanism by which 2-DG inhibits the progression of cervical cancer in vitro, elucidated the interregulation between glycolysis and Wnt/β-catenin signaling, and preliminarily explored the effect of combined targeting of glycolysis and Wnt/β-catenin signaling on cell proliferation, which provides more possibilities for the formulation of subsequent clinical treatment strategies.