MDM2 as a target for ellagic acid­mediated suppression of prostate cancer cells in vitro.

Prostate cancer (PCa) is the most common cancer in men. Despite the available treatments for PCa, a significant number of patients relapse as the disease becomes hormonal­independent. p53 is a common tumor suppressor; however, its activity is diminished via the overexpression of murine double minute­2 (MDM2). The pomegranate, walnuts, and blueberries are widely consumed fruits and nuts that contain several polyphenolic compounds, mainly ellagic acid (EA). The present study focused on the influence of EA on the p53/MDM2 pathway in PCa cell lines. Three human PCa cell lines PCa LNCaP (p53+/+), 22RV1 (p53-/+), and PC3 (p53-/-) harboring different p53 genotypes were used in this research. We found that EA downregulated the gene and protein expression levels of MDM2 and increased the protein expression of p53 as determined by qPCR and western blot analyses. Moreover, by using western blot analysis, we determined that EA increased the protein expression of the p53 target proteins p21, p53 upregulated modulator of apoptosis (PUMA) [also known as Bcl­2­binding component 3 (BBC3)] and Phorbol­12­myristate­13­acetate­induced protein 1 (NOXA). Furthermore, we found that EA induced apoptosis in the absence of p53 by downregulating MDM2 and X­linked inhibitor of apoptosis protein (XIAP) protein expressions as determined by western blot analysis. We conclude that EA suppressed PCa cells in vitro partly by downregulating MDM2.