2-Deoxy-D-glucose simultaneously targets glycolysis and Wnt/ß-catenin signaling to inhibit cervical cancer progression.

ABSTRACT

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)/ß-catenin signaling. Mechanistically, 2-DG accelerated the degradation of ß-catenin protein, which resulted in the decrease of ß-catenin expression in both nucleus and cytoplasm. The Wnt agonist lithium chloride and ß-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/ß-catenin signaling. As expected, the combination of 2-DG and Wnt inhibitor synergistically inhibited cell growth. It is noteworthy that, down-regulation of Wnt/ß-catenin signaling also inhibited glycolysis, indicating a similar positive feedback regulation between glycolysis and Wnt/ß-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/ß-catenin signaling, and preliminarily explored the effect of combined targeting of glycolysis and Wnt/ß-catenin signaling on cell proliferation, which provides more possibilities for the formulation of subsequent clinical treatment strategies.