This study aimed to demonstrate that
ginsenoside compound K (20 (S)-
ginsenoside CK; CK) downregulates Bcl-2-associated
transcription factor 1 (Bclaf1), which inhibits the
hypoxia-inducible factor-1α (HIF-1α)-mediated glycolysis pathway to inhibit the proliferation of
liver cancer cells. Treatment of
hepatoma cells (Bel-7404 and Huh7) under hypoxic conditions with different concentrations of CK showed that CK inhibited the proliferation of
hepatoma cells in a time- and concentration-dependent manner; furthermore, the ability of the cells to form colonies was reduced, and cell growth was blocked in the G0/G1 phase. CK promoted the degradation of HIF-1α ubiquitination in
liver cancer cells by regulating the expression of HIF-1α and related ubiquitination
proteins; moreover, it reduced the activity of key
enzymes involved in glycolysis, the pressure of cellular glycolysis, and the rate of real-time
ATP production, thereby inhibiting the glycolysis pathway. It also decreased the expression of Bclaf1 in hypoxic
liver cancer cells and thus reduced the ability of Bclaf1 to bind to HIF-1α. CK treatment of Bel-7404 and Huh7 cells with CRISPR/Cas9-engineered knock out of Bclaf1 gene under hypoxic conditions further suppressed the expression of HIF-1α, promoted HIF-1α ubiquitination, and inhibited the glycolysis pathway. In a rat model of primary
liver cancer induced by
diethylnitrosamine, positron emission tomography and computed tomography scans showed that after CK administration,
tumor tissue volumes were reduced and
glucose uptake capacity decreased. Increased Bclaf1 and HIF-1α expression promoted the ubiquitination of HIF-1α and inhibited the glycolysis pathway, thereby inhibiting the proliferation of
liver cancer cells. In summary, this study confirmed by in vitro and in vivo experiments that in hypoxic
liver cancer cells CK downregulates the expression of Bclaf1, inhibits the HIF-1α-mediated glycolysis pathway, and inhibits cell proliferation, suggesting that the CK-mediated effects on Bclaf1 may represent a novel therapeutic approach for the treatment of
liver cancer patients.