Abstract
Epigallocatechingallate (EGCG) is a major bioactive component of green tea and is associated with health benefits against multiple diseases including cancer. As an indicator of hepatocellular carcinoma (HCC), high levels of α-fetal protein (AFP) are related to malignant differentiation and poor prognosis of cancer cells. In this study, EGCG can effectively reduce AFP secretion and simultaneously induce AFP aggregation in human HCC HepG2 cells. EGCG-stimulated autophagy induces the degradation of AFP aggregates in HepG2 cells. Furthermore, we thoroughly studied the underlying molecular mechanisms behind EGCG-stimulated autophagy by using large-scale all-atom molecular dynamics simulations, which revealed a novel molecular mechanism. EGCG directly interacts with LC3-I protein, readily exposing the pivotal Gly-120 site of the latter to other important binding partners such as 1,2-distearoyl-sn-glycero-3-phosphoethanolamine and promoting the synthesis of LC3-II, a characteristic autophagosomal marker. Our results suggest that EGCG is critical in regulating AFP secretion and in modulating autophagic activities of HepG2 cells, providing a molecular basis for potentially preventing and treating HCC.
Highlights
Autophagy is pivotal in various physiological processes
EGCG promotes apoptosis and autophagy in oral cancer SSC-4 cells,[10] and on the other hand, autophagy inhibition contributes to the synergy between EGCG and doxorubicin in a combined treatment of hepatoma Hep3B cells.[11]
We hypothesized that EGCG possibly inhibited AFP secretion by causing an energy shortage in the mitochondria and a deficiency of motion-dependent matrix in the cytoskeleton (Supplementary Figure S2 and Figure 6)
Summary
As a highly conserved degradation process of injured protein, lipid, and organelle, autophagy participates in cell growth, development, and death.[1] Autophagy is a necessary process in bone growth,[2] while suppression of autophagy was related to pathologies, such as cancer.[3] Traditionally, autophagosomal membrane formation is a key process during early autophagic stages. During this process, the microtubule-associated protein 1A/1B-light chain 3 (LC3-I) connects to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) through an amide bond with the Gly-120 residue located in the C-terminal region of the former.
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