Oleuropein and hydroxytyrosol activate GPER/ GPR30-dependent pathways leading to apoptosis of ER-negative SKBR3 breast cancer cells
Article first published online: 9 SEP 2013
© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Molecular Nutrition & Food Research
Volume 58, Issue 3, pages 478–489, March 2014
How to Cite
Chimento, A., Casaburi, I., Rosano, C., Avena, P., De Luca, A., Campana, C., Martire, E., Santolla, M. F., Maggiolini, M., Pezzi, V. and Sirianni, R. (2014), Oleuropein and hydroxytyrosol activate GPER/ GPR30-dependent pathways leading to apoptosis of ER-negative SKBR3 breast cancer cells. Mol. Nutr. Food Res., 58: 478–489. doi: 10.1002/mnfr.201300323
- Issue published online: 4 MAR 2014
- Article first published online: 9 SEP 2013
- Manuscript Accepted: 30 JUL 2013
- Manuscript Revised: 3 JUL 2013
- Manuscript Received: 2 MAY 2013
- Associazione Italiana per la Ricerca sul Cancro (AIRC). Grant Number: IG10344
- SPREAD BIO-OIL. Grant Number: 010293
- Breast cancer;
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.
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.