EGCG inhibits protein synthesis, lipogenesis, and cell cycle progression through activation of AMPK in p53 positive and negative human hepatoma cells

Abstract

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.

Epigallocatechin-3-gallate inhibits cell growth, induces apoptosis and causes S phase arrest in hepatocellular carcinoma by suppressing the AKT pathway

“…Cells are arrested in G1, S and G2/M phases to prevent replication of damaged DNA or to prevent aberrant mitosis. Previous studies reported that EGCG blocked progression of the cell cycle at G1 phase in HCC lines (12), which is reportedly related to the activation of AMPK (12). However, we found that EGCG caused S phase but not G1 arrest in SMMC7721 cells (Fig.…”

“…EGCG inhibited the growth and metastasis of pancreatic cancer (7,8) and colorectal cancer (9), reduced the incidence of esophageal cancer (10) and improved the prognosis of breast cancer (11). It also inhibited the growth of HepG2 cells (12).…”

Preventive Effects of (−)-Epigallocatechin Gallate on Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BL/KsJ-db/db Mice

“…Furthermore, in addition to the improvement of metabolic disorders, activation of AMPK by EGCG also positively contributes to the prevention of hepatotumorigenesis because decreased AMPK activation is implicated in tumor development and therefore may be a tumor suppressor and a promising target for cancer chemoprevention (38). In fact, EGCG has been shown to inhibit lipogenesis and cellcycle progression through the activation of AMPK in human HCC-derived cells (39). The phosphorylation of LKB1, which is a tumor suppressor protein and a major AMPK kinase (38), is also increased by EGCG (37).…”

20(S)-Ginsenoside Rg3-induced apoptosis in HT-29 colon cancer cells is associated with AMPK signaling pathway

“…recently, aMPK was shown to be involved in cellular homeostasis and emerged as a pivot point between cell survival and apoptosis (16)(17)(18). Previous studies have reported that aMPK activation regulates apoptosis in cancer cells via a signaling pathway that includes the up-regulation of p53 protein, activation of caspases, generation of roS and inhibition of the proteolytic cleavage of poly (adP-ribose) polymerase (ParP)-lKB1 (17)(18)(19)(20).…”