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MDM2 as a target for ellagic acid‑mediated suppression of prostate cancer cells in vitro
Yasir I Mohammed Saleem1, Mustafa I Selim1
1Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA.
Abstract:
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 hormonal‑independent. p53 is a common tumor suppressor; however, its activity is diminished via the overexpression of murine double minute‑2 (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 Bcl‑2‑binding component 3 (BBC3)] and Phorbol‑12‑myristate‑13‑acetate‑induced protein 1 (NOXA). Furthermore, we found that EA induced apoptosis in the absence of p53 by downregulating MDM2 and X‑linked 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.
Insights
Ellagic acid (EA), found in pomegranates and walnuts, suppresses prostate cancer (PCa) by downregulating murine double minute-2 (MDM2) and increasing tumor suppressor p53 protein levels, promoting cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Nutritional Science
Background:
- Prostate cancer (PCa) is a leading cancer in men, with relapse often occurring due to hormonal independence.
- The tumor suppressor p53's activity is frequently inhibited by the overexpression of murine double minute-2 (MDM2).
- Ellagic acid (EA), a polyphenol in fruits like pomegranate and nuts like walnuts, is investigated for its anti-cancer properties.
Purpose of the Study:
- To investigate the effect of ellagic acid (EA) on the p53/MDM2 pathway in human prostate cancer (PCa) cell lines.
- To determine if EA can modulate the expression of key proteins involved in PCa progression and apoptosis.
Main Methods:
- Utilized three human PCa cell lines (LNCaP, 22RV1, PC3) with varying p53 genotypes.
- Employed quantitative PCR (qPCR) and western blot analyses to assess gene and protein expression levels.
- Measured the expression of MDM2, p53, p21, PUMA (BBC3), NOXA, and XIAP proteins.
Main Results:
- EA significantly downregulated both gene and protein expression of MDM2 in PCa cell lines.
- EA increased the protein expression of the tumor suppressor p53 and its downstream targets: p21, PUMA, and NOXA.
- EA induced apoptosis in p53-deficient PCa cells by downregulating MDM2 and XIAP.
Conclusions:
- Ellagic acid (EA) demonstrates a suppressive effect on prostate cancer (PCa) cells in vitro.
- EA exerts its anti-cancer effects partly through the downregulation of MDM2, thereby modulating the p53 pathway.
- EA's ability to induce apoptosis, even in the absence of functional p53, highlights its therapeutic potential.
