Two novel GPER agonists induce gene expression changes and growth effects in cancer cells

R. Lappano, C. Rosano, M. F. Santolla, M. Pupo, E. M. de Francesco, P. de Marco, M. Ponassi, A. Spallarossa, A. Ranise, M. Maggiolini

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)531-542
Number of pages12
JournalCurrent Cancer Drug Targets
Volume12
Issue number5
Publication statusPublished - Jun 2012

Fingerprint

Estrogen Receptors
Gene Expression
Growth
Neoplasms
Estrogens
MAP Kinase Signaling System
Gene Silencing
Endometrial Neoplasms
G-Protein-Coupled Receptors
Immunoblotting
Transcriptional Activation
Transfection
Real-Time Polymerase Chain Reaction
Breast
Up-Regulation
Pharmacology
Technology
Genes

Keywords

  • Breast cancer cells
  • Endometrial cancer cells
  • Estrogen receptors
  • GPER-L1
  • GPER-L2
  • GPR30/GPER

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Cancer Research

Cite this

Lappano, R., Rosano, C., Santolla, M. F., Pupo, M., de Francesco, E. M., de Marco, P., ... Maggiolini, M. (2012). Two novel GPER agonists induce gene expression changes and growth effects in cancer cells. Current Cancer Drug Targets, 12(5), 531-542.

Two novel GPER agonists induce gene expression changes and growth effects in cancer cells. / Lappano, R.; Rosano, C.; Santolla, M. F.; Pupo, M.; de Francesco, E. M.; de Marco, P.; Ponassi, M.; Spallarossa, A.; Ranise, A.; Maggiolini, M.

In: Current Cancer Drug Targets, Vol. 12, No. 5, 06.2012, p. 531-542.

Research output: Contribution to journalArticle

Lappano, R, Rosano, C, Santolla, MF, Pupo, M, de Francesco, EM, de Marco, P, Ponassi, M, Spallarossa, A, Ranise, A & Maggiolini, M 2012, 'Two novel GPER agonists induce gene expression changes and growth effects in cancer cells', Current Cancer Drug Targets, vol. 12, no. 5, pp. 531-542.
Lappano R, Rosano C, Santolla MF, Pupo M, de Francesco EM, de Marco P et al. Two novel GPER agonists induce gene expression changes and growth effects in cancer cells. Current Cancer Drug Targets. 2012 Jun;12(5):531-542.
Lappano, R. ; Rosano, C. ; Santolla, M. F. ; Pupo, M. ; de Francesco, E. M. ; de Marco, P. ; Ponassi, M. ; Spallarossa, A. ; Ranise, A. ; Maggiolini, M. / Two novel GPER agonists induce gene expression changes and growth effects in cancer cells. In: Current Cancer Drug Targets. 2012 ; Vol. 12, No. 5. pp. 531-542.
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