Figure 5.

Mechanism of genistein-mediated inhibition of glycolysis and induction of apoptosis in HCC cells. Inhibition of HIF1-α by genistein led to the suppression of high GLUT1 and HK2 expression in sorafenib-resistant HCC cells, resulting in the suppression of ATP production. In addition, disruption of the HK2/VDAC complex led to mitochondrial membrane potential loss, resulting in cell death. Inhibition of HIF1-α activated the pro-apoptotic proteins Bax and Bak, as well as the cleavage of Bid, which interacts with the anti-apoptotic Bcl-2 family proteins Bcl-2 and Bcl-xl to relieve their apoptosis-inhibitory effect. Apoptogenic substrates were thus released from the mitochondria, such as cytochrome c into the cytoplasm and apoptosis-inducing factor (AIF) to the nucleus, causing caspase activation and cell apoptosis, and therefore restoring the sensitivity to sorafenib.