Autophagy and glycolysis independently attenuate silibinin-induced apoptosis in human hepatocarcinoma HepG2 and Hep3B cells

Purpose: The mechanism of cytotoxicity of silibinin on two human hepatocellular carcinoma (HCC) cell lines, HepG2 (p53 wild-type) and Hep3B cells (p53 null), is examined in relation with the induction of autophagy and phosphorylation of AMP-activated protein kinase (p-AMPK). Materials and Methods: Levels of apoptosis in relation to the levels of autophagy and those of glycolysis-related proteins, glucose transporter 1/4 (Glut1/4) and hexokinase-II (HK2), in HepG2 and Hep3B cells were examined. Results: Silibinin-induced apoptosis was incomplete for HCC cell death in that up-regulated autophagy and/or reduced level of glycolysis, which are induced by silibinin treatment, antagonized silibinin-induced apoptosis. Inhibition of autophagy with 3-methyl adenine (3MA) or blocking of AMP-activated protein kinase (AMPK) activation with Compound C (CC) enhanced silibinin-induced apoptosis. The results confirm that AMPK involved in autophagy as well as in glycolysis remaining with silibinin is responsible for attenuation of silibinin-induced apoptosis. Blocking of AMPK or autophagy contributes to the enhancement of silibinin's cytotoxicity to HepG2 and Hep3B cells. Conclusion: This study shows that incomplete apoptosis of HCC by silibinin treatment becomes complete by repression of autophagy and/or glycolysis.

Automated summary

The study found that silibinin-induced apoptosis in HCC cells was incomplete, as up-regulated autophagy and reduced glycolysis were involved. Inhibiting autophagy or AMP-activated protein kinase activation enhanced the cytotoxicity of silibinin, suggesting that blockage of autophagy and glycolysis can lead to complete apoptosis of HCC cells treated with silibinin.