Abstract
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.
Highlights
Primary liver cancer is among the most common malignant tumors, with the sixth highest incidence and second highest mortality rate worldwide (Gao et al, 2017; Shen et al, 2017)
We investigated the effects of compound K (CK) on the proliferation of hepatoma cells under hypoxic conditions
The expression of key glycolytic proteins and the CCK8 assay results after hypoxiainducible factor-1α (HIF-1α) knockout were consistent with those obtained after knocking out Bcl-2-associated transcription factor 1 (Bclaf1). These results suggested that CK promoted the ubiquitination of HIF-1α in hypoxic liver cancer cells, and that the glycolysis pathway that inhibits proliferation may be mediated by HIF-1α regulation of Bclaf1, with Bclaf1 knockout further promoting the action of CK
Summary
Primary liver cancer is among the most common malignant tumors, with the sixth highest incidence and second highest mortality rate worldwide (Gao et al, 2017; Shen et al, 2017). Hepatocellular carcinoma is the most common type of primary liver cancer. Treatments for hepatocellular carcinoma include surgical resection, radiation therapy, chemotherapy, and liver transplantation. Owing to the non-specific symptoms of liver cancer, most cases are diagnosed in the middle and late stages of the disease. Treatment for patients with advanced liver cancer is limited and prone to drug resistance (Bhayani et al, 2015). There is a need for new chemotherapy drugs or targeted therapies
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