Genistein suppresses aerobic glycolysis and induces hepatocellular carcinoma cell death.

ABSTRACT:

Background

Genistein is a natural isoflavone with many health benefits, including antitumour effects. Increased hypoxia-inducible factor 1 ? (HIF-1?) levels and glycolysis in tumour cells are associated with an increased risk of mortality, cancer progression, and resistance to therapy. However, the effect of genistein on HIF-1? and glycolysis in hepatocellular carcinoma (HCC) is still unclear.

Methods

Cell viability, apoptosis rate, lactate production, and glucose uptake were measured in HCC cell lines with genistein incubation. Lentivirus-expressed glucose transporter 1 (GLUT1) or/and hexokinase 2 (HK2) and siRNA of HIF-1? were used to test the direct target of genistein. Subcutaneous xenograft mouse models were used to measure in vivo efficacy of genistein and its combination with sorafenib.

Results

Genistein inhibited aerobic glycolysis and induced mitochondrial apoptosis in HCC cells. Neither inhibitors nor overexpression of HK2 or GLUTs enhance or alleviate this effect. Although stabiliser of HIF-1? reversed the effect of genistein, genistein no longer has effects on HIF-1? siRNA knockdown HCC cells. In addition, genistein enhanced the antitumour effect of sorafenib in sorafenib-resistant HCC cells and HCC-bearing mice.

Conclusions

Genistein sensitised aerobic glycolytic HCC cells to apoptosis by directly downregulating HIF-1?, therefore inactivating GLUT1 and HK2 to suppress aerobic glycolysis. The inhibitory effect of genistein on tumour cell growth and glycolysis may help identify effective treatments for HCC patients at advanced stages.

SUBMITTER: Li S 

PROVIDER: S-EPMC5680469 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature