Dioscin Inhibited Glycolysis and Induced Cell Apoptosis in Colorectal Cancer via Promoting c-myc Ubiquitination and Subsequent Hexokinase-2 Suppression

摘要

Purpose: Dioscin is a natural product isolated from traditional Chinese medicines and is reported to have antitumor activities against several cancers. In the present study, we aimed to investigate its potency against colorectal cancers, especially the effects on tumor glycolysis, and to elaborate related molecular mechanisms. Methods: The antitumor activities of dioscin were evaluated by cell proliferation assays and colony formation assays in vitro and the mouse xenograft models in vivo. The effects of dioscin on tumor glycolysis were determined by measuring glucose absorption and lactate generation. Cell apoptosis was detected by cleaved PARP and the activity of caspase-3. Protein overexpression or gene knockdown was conducted to illustrate molecular mechanisms. Immunoprecipitation experiments were applied to identify the interaction between different proteins. Results: Dioscin substantially inhibited colorectal cancer cell proliferation in vitro and suppressed the xenograft growth in nude mice. After dioscin treatment, with the suppression of hexokinase-2, the tumor glycolysis was significantly decreased. Dioscin substantially impaired the interaction between hexokinase-2 and VDAC-1, and induced cell apoptosis. Exogenous overexpression of hexokinase-2 significantly antagonized the glycolysis suppression and apoptosis induction by dioscin. Through enhancing the binding of E3 ligase FBW7 to c-myc, dioscin promoted the ubiquitination of c-myc and gave rise to c-myc degradation, which contributed to the inhibition of hexokinase-2. Conclusion: Our studies revealed a novel mechanism by which dioscin exerted its antitumor activity in colorectal cancer, and verified that dioscin or its analog might have potentials for colorectal cancer therapy.