Oleuropein and hydroxytyrosol activate GPER/ GPR30-dependent pathways leading to apoptosis of ER-negative SKBR3 breast cancer cells.

Abstract

SCOPE:

We have previously demonstrated that oleuropein (OL) and hydroxytyrosol (HT) reduce 17β-estradiol-mediated proliferation in MCF-7 breast cancer (BC) cells without affecting the classical genomic action of estrogen receptor (ER), but activating instead the ERK1/2 pathway. Here, we hypothesized that this inhibition could be mediated by a G-protein-coupled receptor named GPER/GPR30. Using the ER-negative and GPER-positive SKBR3 BC cells as experimental model, we investigated the effects of OL and HT on GPER-mediated activation of downstream pathways.

METHODS AND RESULTS:

Docking simulations and ligand-binding studies evidenced that OL and HT are able to bind GPER. MTT cell proliferation assays revealed that both phenols reduced SKBR3 cell growth; this effect was abolished silencing GPER. Focusing on OL and HT GPER-mediated pathways, using Western blot analysis we showed a sustained ERK1/2 activation triggering an intrinsic apoptotic pathway.

CONCLUSION:

Showing that OL and HT work as GPER inverse agonists in ER-negative and GPER-positive SKBR3 BC cells, we provide novel insights into the potential of these two molecules as tools in the therapy of this subtype of BC.

• Authors: Adele Chimento, Ivan Casaburi, Camillo Rosano, Paola Avena, Arianna De Luca, Carmela Campana, Emilia Martire, Maria Francesca Santolla, Marcello Maggiolini, Vincenzo Pezzi, Rosa Sirianni
• Journal: Molecular nutrition & food research (Mol Nutr Food Res) Vol. 58 Issue 3 Pg. 478-89 (Mar 2014) ISSN: 1613-4133 [Electronic] Germany
• PMID: 24019118 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• GPER1 protein, human
• Iridoid Glucosides
• Iridoids
• Receptors, Estrogen
• Receptors, G-Protein-Coupled
• 3,4-dihydroxyphenylethanol
• oleuropein
• Extracellular Signal-Regulated MAP Kinases
• Phenylethyl Alcohol

Topics

• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Humans
• Iridoid Glucosides
• Iridoids (pharmacology)
• Phenylethyl Alcohol (analogs & derivatives, pharmacology)
• Receptors, Estrogen (genetics, metabolism)
• Receptors, G-Protein-Coupled (genetics, metabolism)
• Signal Transduction (drug effects)
• Tumor Cells, Cultured