The p53 protein has been dubbed as the “guardian of the genome,” not to be confused with the movie Guardians of the Galaxy. However, you may say p53 has some superhero qualities by protecting and fighting for good. The p53 gene is a tumor suppressor gene that plays a critical role in preventing cells with DNA damage or other cellular insults from turning cancerous. Researchers have tried to combat cancer by boosting the number of copies of healthy p53 in cells, and get a better understanding of its tumor-suppressing function. Now, a new study by researchers at the Rensselaer Polytecnhic Institute reports an antioxidant found in green tea may lend a hand by increasing levels of p53. Their study points to a new target for cancer drug discovery.
Their findings are published in Nature Communications in a paper titled, “EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction.”
The researchers found that the antioxidant, epigallocatechin gallate (EGCG) may be able to boost p53’s anticancer activity. “EGCG from green tea can induce apoptosis in cancerous cells, but the underlying molecular mechanisms remain poorly understood,” the researchers wrote. “Using SPR and NMR, here we report a direct, μM interaction between EGCG and the tumor suppressor p53 (KD = 1.6 ± 1.4 μM), with the disordered N-terminal domain (NTD) identified as the major binding site (KD = 4 ± 2 μM).”
Green tea’s impact on cancer has been mixed, but has been known to aid healthy cells in all stages of growth.
“Both p53 and EGCG molecules are extremely interesting. Mutations in p53 are found in over 50% of human cancer, while EGCG is the major antioxidant in green tea, a popular beverage worldwide,” explained Chunyu Wang, MD, PhD, corresponding author and a professor of biological sciences at Rensselaer Polytechnic Institute. “Now we find that there is a previously unknown, direct interaction between the two, which points to a new path for developing anticancer drugs. Our work helps to explain how EGCG is able to boost p53’s anticancer activity, opening the door to developing drugs with EGCG-like compounds.”
The researchers found that the interaction between EGCG and p53 preserves the protein from degradation. After being produced in the body, p53 is quickly degraded when the N-terminal domain interacts with a protein called MDM2.
“Both EGCG and MDM2 bind at the same place on p53, the N-terminal domain, so EGCG competes with MDM2,” said Wang. “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 anticancer function. This is a very important interaction.”
Their work provides insights into the mechanisms for EGCG’s anticancer activity and identifies p53 N-terminal domain as a target for cancer drug discovery.
“By developing an understanding of the molecular-level mechanisms that control key biochemical interactions linked to devastating illnesses such as cancer and Alzheimer’s disease, Chunyu’s research is laying the groundwork for new and successful therapies,” concluded Curt Breneman, PhD, dean of the Rensselaer School of Science.