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The ellagitannin colonic metabolite urolithin D selectively inhibits EphA2 phosphorylation in prostate cancer cells
Author(s) -
Giorgio Carmine,
Mena Pedro,
Del Rio Daniele,
Brighenti Furio,
Barocelli Elisabetta,
HassanMohamed Iftiin,
Callegari Donatella,
Lodola Alessio,
Tognolini Massimiliano
Publication year - 2015
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.201500470
Subject(s) - ellagitannin , ellagic acid , metabolite , ephrin , erythropoietin producing hepatocellular (eph) receptor , chemistry , biochemistry , pharmacology , receptor , cytotoxicity , biology , in vitro , antioxidant , polyphenol , receptor tyrosine kinase
Scope The Eph‐ephrin system comprises emerging proteins involved in many pathophysiological processes. The pharmacological activity of the main metabolites derived from the intake of some classes of (poly)phenolic compounds, such as caffeoylquinic acids, flavan‐3‐ols, and ellagitannins, on the Eph‐ephrin interaction was evaluated at physiological concentrations. Functional studies to elucidate their role in prostate cancer were also performed. Methods and results Among the 21 phenolics screened by an ELISA‐binding assay, just urolithin C, urolithin D, and ellagic acid succeeded to inhibit the EphA2‐ephrin‐A1 binding. Urolithin D, the most active, was a competitive and reversible antagonist of EphA receptors able to discriminate between EphA and EphB receptors, showing intra‐classes selectivity. Molecular modeling and structure–activity relationships shed light on the binding mode and selective activity of urolithin D. This catabolite blocked EphA2 phosphorylation mediated by ephrin‐A1, while lacking cytotoxicity and anti‐proliferative effects, and was inactive on the EphA2 kinase assay. Conclusion The mechanisms behind the cancer preventive properties of foods rich in flavan‐3‐ols and caffeoylquinic acids are not associated with metabolic pathways directly linked to the Eph‐ephrin system. However, the ellagitannin‐derived colonic metabolite urolithin D was able to exert remarkable and selective EphA‐ephrin‐A inhibition, which might impact on prostate cancer prevention.