A new study, published in Nature Communications, has provided insights into the mechanisms of a compound in green tea and its interaction with p53 – offering a new lead for cancer drug discovery.
In recent years, diet-based cancer prevention and therapy have received considerable attention. Green tea in particular has been reported to have inhibitory effects against various types of cancer. These include breast, lung, prostate and colon cancers. Most of the chemo-preventive effects of green tea are attributed to polyphenol compounds – the most important being epigallocatechin-3-gallate (EGCG). EGCG accounts for 50–80% of the catechin in green tea.
In EGCG-induced apoptosis and cell growth arrest, researchers have found that p53 plays an important role. p53 is often referred to as the ‘guardian of the genome’. It is a critical tumour suppressor that is mutated in over 50% of human cancers. It specifically promotes cell-cycle arrest or apoptosis as a response to cellular stress stimuli. p53 interacts directly with anti-apoptotic proteins to induce apoptosis and is also involved in the anti‑senescent effects of EGCG.
The EGCG-p53 interaction
In this study, researchers used surface plasmon resonance (SPR) and nuclear magnetic resonance (NMR) to report a direct interaction between EGCG and p53. The team identified the disordered N-terminal domain (NTD) as the major binding site.
They found that the EGCG-p53 interaction disrupts p53 interactions with its regulatory E3 ligase MDM2. It also inhibits ubiquitination of p53 by MDM3, likely stabilising p53 for anti-tumour activity.
Chunyu Wang, corresponding author, stated:
“Both EGCG and MDM2 bind at the same place on p53, the N-terminal domain, so EGCG competes with MDM2.
When EGCG binds with p53, the protein is not being degraded through MDM2, so the level of p53 will increase with the direct interaction with EGCG, and that means there is more p53 for anti-cancer function. This is a very important interaction.”
This work provides insights into the mechanisms for EGCG’s anticancer activity. It also has identified p53 NTD as a potential target for cancer drug discovery through dynamic interactions with small molecules.
Image credit: By valeria_aksakova – freepik