title: Oleuropein and hydroxytyrosol activate GPER/ GPR30-dependent pathways leading to apoptosis of ER-negative SKBR3 breast cancer cells.
abstract: METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Pharmacy, Health and Nutrition Sciences, University of Calabria, Cosenza, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: Chimento
authors.forename: Ivan
authors.initials: I
authors.lastname: Casaburi
authors.forename: Camillo
authors.initials: C
authors.lastname: Rosano
authors.forename: Paola
authors.initials: P
authors.lastname: Avena
authors.forename: Arianna
authors.initials: A
authors.lastname: De Luca
authors.forename: Carmela
authors.initials: C
authors.lastname: Campana
authors.forename: Emilia
authors.initials: E
authors.lastname: Martire
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Santolla
authors.forename: Marcello
authors.initials: M
authors.lastname: Maggiolini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Pezzi
authors.forename: Rosa
authors.initials: R
authors.lastname: Sirianni
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D057888:Iridoid Glucosides; D039823:Iridoids / Q000494:pharmacology*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: C109584:GPER1 protein, human; D057888:Iridoid Glucosides; D039823:Iridoids; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; C005975:3,4-dihydroxyphenylethanol; C002769:oleuropein; D048049:Extracellular Signal-Regulated MAP Kinases; D010626:Phenylethyl Alcohol
keywords: Apoptosis; Breast cancer; GPER; Hydroxytyrosol; Oleuropein; SKBR3