MOLECULAR MECHANISM OF ELLAGIC ACID AND UROLITHIN A IN THE SUPPRESSION OF PROSTATE CANCER BY INFLUENCING THE p53-MDM2 PATHWAY

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Yasir Ihsan Mohammed Saleem (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Carcinoma of the prostate (CaP) is the most common cancer in men and the second leading cause of cancer-related death in men worldwide. Despite the available treatments for CaP including surgery and Androgen deprivation therapy (ADT) , 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 tumor suppressor that mediates apoptosis , cell cycle arrest and DNA repair. 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 , leading CaP cells to undergo uncontrolled cell growth and cancer progression. 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 when 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.

Additional Information

Publication

Dissertation

Language: English

Date: 2019

Keywords

polyphenols, urolithin a

Subjects

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