Green tea compound helps p53, ‘guardian of the genome’ and tumor suppressor

An antioxidant found in green tea can increase levels of p53, a natural anti-cancer protein known as the “guardian of the genome” for its ability to repair DNA damage or destroy cancer cells. Published today in Nature Communications, a study of the direct interaction between p53 and the green tea compound, epigallocatechin gallate (EGCG), points to a new target for the discovery of cancer drugs.

“Both p53 and EGCG molecules are extremely interesting. Mutations in p53 are found in more than 50% of human cancers, while EGCG is the main antioxidant in green tea, a popular drink worldwide,” said Chunyu Wang, corresponding author and professor of biological sciences at Rensselaer Polytechnic Institute. “Now we are discovering that there is a previously unknown, direct interaction between the two, pointing to a new path for the development of anti-cancer drugs. Our work helps to explain how EGCG can stimulate the anti-cancer activity of p53 by opening the door.” to develop drugs with EGCG-like compounds. “

Wang, a member of the Rensselaer Center for Biotechnology and Interdisciplinary Studies, is an expert in the use of nuclear magnetic resonance spectroscopy to study specific mechanisms in Alzheimer’s disease and cancer, including p53, which he described as “perhaps the most important protein. in cancer in humans. “

P53 has several known anti-cancer functions, including stopping cell growth to allow DNA repair, activating DNA repair, and initiating programmed cell death – called apoptosis – when DNA damage cannot be repaired. One end of the protein, known as the N-terminal domain, has a flexible shape and can therefore potentially perform multiple functions depending on how multiple molecules interact.

EGCG is a natural antioxidant, which means that it helps reverse the near-constant damage caused by oxygen metabolism. EGCG is abundant in green tea and is also packaged as an herbal supplement.

Wang’s team found that the interaction between EGCG and p53 protects the protein from degradation. Typically, after it is produced in the body, p53 is rapidly degraded when the N-terminal domain interacts with the protein MDM2. This regular cycle of production and degradation keeps p53 levels at a low constant.

“Both EGCG and MDM2 bind at the same site on p53, the N-terminal domain, so EGCG competes with MDM2,” Wang said. “When EGCG binds to p53, the protein is not degraded by MDM2, so the level of p53 will increase with the direct interaction with EGCG, meaning there is more p53 for anti-cancer function. This is a very important interaction.”

“EGCG binds intrinsically disrupted p53 N-terminal domain and disrupts p53-MDM2 interaction” was published with support from multiple National Institutes of Health fellowships. At Rensselaer, Wang was joined on the investigation by Lauren Gandy, Weihua Jin, Lufeng Yan, Xinyue Liu and Yuanyuan Xiao. First author Jing Zhao is a former member of Wang’s laboratory, now on the faculty of China Agricultural University in Beijing, China. Co-lead author Alan Blaney is an MD-Ph.D. student at Upstate Medical University. Researchers also contributed from the SUNY Upstate Medical Center; the University of Massachusetts, Amherst; New York University; New York State University at Binghamton; NYU Shanghai; and Merck Research Laboratories.