EGCG inhibits protein synthesis, lipogenesis, and cell cycle progression through activation of AMPK in p53 positive and negative human hepatoma cells.
In the previous studies, (-)-epigallocatechin-3-gallate (EGCG) has been shown to have anticarcinogenic effects via modulation in protein expression of p53. Using p53 positive Hep G2 and p53 negative Hep 3B cells, we found that treatment of EGCG resulted in dose-dependent inhibition of cellular proliferation, which suggests that the interaction of EGCG with p53 may not fully explain its inhibitory effect on proliferation. Caloric restriction (CR) reduces the incidence and progression of spontaneous and induced tumors in laboratory rodents. EGCG has multiple beneficial activities similar to those associated with CR. One key enzyme thought to be activated during CR is AMP-activated kinase (AMPK), a sensor of cellular energy levels. Here, we showed that EGCG activated AMPK in both p53 positive and negative human hepatoma cells. The activation of AMPK suppressed downstream substrates, such as mammalian target of rapamycin (mTOR) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1) and a general decrease in mRNA translation. Moreover, EGCG activated AMPK decreases the activity and/or expression of lipogenic enzymes, such as fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC). Interestingly, the decision between apoptosis and growth arrest following AMPK activation is greatly influenced by p53 status. In p53 positive Hep G2 cells, EGCG blocked the progression of cell cycle at G1 phase by inducing p53 expression and further up-regulating p21 expression. However, EGCG inducted apoptosis in p53 negative Hep 3B cells. Based on these results, we have demonstrated that EGCG has a potential to be a chemoprevention and anti-lipogenesis agent for human hepatoma cells.
Huang
Chi-Hung
CH
Institute of Biochemistry, College of Life Science, National Chung Hsing University, Taichung, Taiwan.
Tsai
Shang-Jie
SJ
Wang
Ying-Jan
YJ
Pan
Min-Hsiung
MH
Kao
Jung-Yie
JY
Way
Tzong-Der
TD
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000235:genetics; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D064429:Fatty Acid Synthases / Q000235:genetics; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects*; D011494:Protein Kinases / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53 / Q000032:analysis* / Q000502:physiology
D016588:Anticarcinogenic Agents; D016159:Tumor Suppressor Protein p53; D002392:Catechin; C045651:epigallocatechin gallate; D064429:Fatty Acid Synthases; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase