Caffeic Acid Phenethyl Ester Inhibits Ubiquitination and Degradation of p53 and Blocks Cervical Cancer Cell Growth.

Abstract

In high-risk human papillomavirus (HR-HPV)-positive cervical cancer, E6-associated protein (E6AP), an E3 ubiquitin ligase, mediates the ubiquitination and proteasomal degradation of the tumor suppressor p53. Here, we addressed the question of whether caffeic acid phenethyl ester (CAPE), a natural product mainly derived from propolis, can disrupt the interaction between E6AP and p53, inhibit ubiquitination degradation of p53 and exhibit anti-cervical cancer activity. The ability of CAPE to inhibit growth and to induce apoptosis was shown in HR-HPV-positive cervical cancer cell lines by performing CCK-8, colony formation and TUNEL assays. Apoptosis-related proteins were tested by western blotting. Coimmunoprecipitation, ubiquitination assay and protein stability assay were carried out to determine whether CAPE can disrupt the E6AP-p53 interaction and inhibit ubiquitination degradation of p53. Our results showed that CAPE inhibits the growth of HR-HPV-positive cervical cancer cells and induces the activation of apoptosis-related pathways. Importantly, CAPE inhibits E6AP expression and disrupts the interaction between E6AP and p53. It inhibits the ubiquitination of p53 and promotes its stabilization. In summary, CAPE has a therapeutic effect on HPV-positive malignant cells, so further studies are needed to assess its clinical application.