title: Two novel GPER agonists induce gene expression changes and growth effects in cancer cells.
abstract: Although the action of estrogens has been traditionally explained by the binding to and transactivation of the nuclear estrogen receptor (ER)α and ERβ, recently the G protein-coupled receptor GPR30/GPER has been involved in the rapid estrogen signaling. We investigated the ability of two original molecules, which were named GPER-L1 and GPERL2, to bind to and activate the GPER transduction pathway in cancer cells. Competition assays, docking simulations, transfection experiments, real-time PCR, immunoblotting, gene silencing technology and growth assays were performed to ascertain the selective action of GPER-L1 and GPER-L2 in activating the GPER-mediated signaling. Both compounds, which did not show any ability to bind to and activate the classical ERs, were able to bind to GPER and to trigger the rapid activation of the GPER/EGFR/ERK transduction pathway which led to the up-regulation of GPER-target genes. Notably, GPER-L1 and GPER-L2 induced the proliferation of SkBr3 breast and Ishikawa endometrial cancer cells at nM concentrations through GPER, hence providing further evidence on their capability to elicit relevant biological responses mediated by GPER. The identification and characterization of these novel compounds as selective GPER agonists represent a valuable tool to further dissect the pharmacology of this novel estrogen receptor and to better differentiate the specific functions elicited by each estrogen receptor subtype in cancer cells.
authors.affiliation: Dipartimento Farmaco- Biologico, Universita della Calabria, Rende, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Lappano
authors.forename: C
authors.initials: C
authors.lastname: Rosano
authors.forename: M F
authors.initials: MF
authors.lastname: Santolla
authors.forename: M
authors.initials: M
authors.lastname: Pupo
authors.forename: E M
authors.initials: EM
authors.lastname: De Francesco
authors.forename: P
authors.initials: P
authors.lastname: De Marco
authors.forename: M
authors.initials: M
authors.lastname: Ponassi
authors.forename: A
authors.initials: A
authors.lastname: Spallarossa
authors.forename: A
authors.initials: A
authors.lastname: Ranise
authors.forename: M
authors.initials: M
authors.lastname: Maggiolini
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics; D047629:Estrogen Receptor beta / Q000096:biosynthesis / Q000235:genetics; D004967:Estrogens / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D011960:Receptors, Estrogen / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; C109584:GPER1 protein, human; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; C512478:EGFR protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases