Carcinoma of the prostate (CaP) is the most common cancer in men and the second leading cause of cancer-related death in men worldwide. Treatment of early stages of CaP often involves the surgical removal of all or part of the prostate gland; whereas malignant cases of advanced CaP generally requires a combination of therapies including removal of the entire prostate, radiotherapy and androgen deprivation. However, significant number of CaP patients relapse the CaP as the disease becomes hormonal independent. Therefore, it is important to target cell death pathways that function independently of androgen signaling. p53 is a common tumor suppressor that mediates apoptosis, cell cycle arrest and DNA repair. Inactivation of p53 is common in CaP cells and this repression of p53 function diminishes androgen receptor signaling. The most common negative regulator of p53 is MDM2, which is itself a target gene of p53 to form an autoregulatory negative feedback loop. MDM2 inhibits p53 transcriptional activity through the induction of p53 polyubiquitination and degradation in the proteasome. This loss of p53 may permit CaP cells to undergo uncontrolled cell growth and cancer progression. Previous studies have shown that certain polyphenols, derived from natural products, possess anticancer activity that may be attributed to their repression of MDM2 ligase activity and activation of p53. Pomegranates, berries, and walnuts contain several bioactive compounds, including the Ellagitannins (ETs). ETs are polyphenolic compounds that are hydrolyzed in the stomach to form Ellagic acid (EA) which is itself metabolized in the gut microbiota to Urolithin A (UA). The purpose of this study was to investigate the influence of EA and UA on the p53-MDM2 signaling pathway in CaP cells. Three models of CaP cell lines were used because each harbor different p53 genotypes: LNCaP (p53+/+), 22RV1(p53-/+) and PC3 (p53-/-). Here we found that, when 22RV1 and LNCaP were treated with EA and UA, the interaction between p53 and MDM2 was disrupted. As a result, both EA and UA caused an increase in p53 protein levels and increased the steady-state concentration of p21, a main downstream target gene of p53 that mediates cell cycle arrest. In addition, EA and UA increased the levels of PUMA and NOXA proteins, both target genes of p53 which confer p53’s pro-apoptotic function. Moreover, we confirmed UA inhibits MDM2-mediated polyubiquitination and degradation of p53. Finally, the data show that EA and UA induce apoptosis in PC3 cells (p53-/-), indicating p53 independent role of these compounds. These results suggest that EA and UA may have potential anti-neoplastic activity in CaP cells that may be at least partially attributed to the stabilization and activation of p53.
Citation Format: Yasir I. Mohammed Saleem, Mustafa Selim. Ellagic acid and its metabolite Urolithin A induce prostate cancer cell death in p53 dependent and independent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2971.