MDM2 as a target for ellagic acid‑mediated suppression of prostate cancer cells in vitro

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.

Ellagic Acid and Cancer Hallmarks: Insights from Experimental Evidence

“…Several studies confirm that EA significantly increases the Bax/Bcl-2 ratio with increasing concentration and exposure time and downregulates Bcl-xL and Mcl-1. EA also increases the expression of Bcl-2 inhibitory proapoptotic proteins PUMA and Noxa in prostate cancer cells [124]. This effect has been demonstrated in prostate cancer cell lines LNCaP (androgen-responsive prostate cancer), ES-2 and PA-1 (human ovarian carcinoma), cervical cancer HeLa cells, and non-small cell lung cancer A549 cells [56,61,115,155].…”

“…Additionally, in the study conducted by Mohammed Saleem and Selim [124] using different models of prostate cancer (LNCaP, p53 +/+ ; 22RV1, p53 −/+ , and PC3, p53 −/− ), EA was reported as effective in reducing MDM2 at the gene and protein levels in all investigated cancer cell lines. These effects were also associated with an enhancement of protein expression of its downstream target p53 in LNCaP and 22RV1, but not in PC3 cells.…”

Chebulinic acid inhibits MDA‐MB‐231 breast cancer metastasis and promotes cell death through down regulation of SOD1 and induction of autophagy

“…Chebulagic acid has been shown to have significant anti angiogenic (Athira et al, 2017) and antitumor activity against colorectal carcinoma and retinoblastoma cell lines (Kumar, Gangappa, Gupta, & Karnati, 2014; Reddy et al, 2009). Similarly, it has been demonstrated that ellagic acid can induce apoptosis in breast, prostrate, colon, and lung cancer cells (Alhakamy et al, 2020, Duan et al, 2020; Mohammed Saleem and Selim, 2020; Yousuf et al, 2020). Gallic acid, another polyphenol present in Triphala preparation also demonstrates significant anticancer and apoptotic activity (Alfei, Marengo, Zuccari, Turrini, & Domenicotti, 2020; Jang, Ko, & Choi, 2020; Patra et al, 2020, Priyadarshi et al, 2020).…”

Berries vs. Disease: Revenge of the Phytochemicals

“…These findings point to the potential of EA to be used not only as a dietary supplement in reducing colon carcinogenesis but also to revert peroxidative toxicities of chemotherapies when used in combinatorial treatment strategies. EA has been implicated in targeting MDM2, which downregulates the action of the p53 tumor suppressor, and treatment could reduce MDM2 and reinduce apoptosis in human prostate cancer cells [ 156 ]. Eskra et al observed that EA and its metabolite urolithin A could reduce prostate cancer cell growth [ 157 ].…”