title: GPER1 is regulated by insulin in cancer cells and cancer-associated fibroblasts.
abstract: Elevated insulin levels have been associated with an increased cancer risk as well as with aggressive and metastatic cancer phenotypes characterized by a poor prognosis. Insulin stimulates the proliferation, migration, and invasiveness of cancer cells through diverse transduction pathways, including estrogen signaling. As G protein estrogen receptor 1 (GPER1) mediates rapid cell responses to estrogens, we evaluated the potential of insulin to regulate GPER1 expression and function in leiomyosarcoma cancer cells (SKUT-1) and breast cancer-associated fibroblasts (CAFs), which were used as a model system. We found that insulin transactivates the GPER1 promoter sequence and increases the mRNA and protein expression of GPER1 through the activation of the PRKCD/MAPK1/c-Fos/AP1 transduction pathway, as ascertained by means of specific pharmacological inhibitors and gene-silencing experiments. Moreover, cell migration triggered by insulin occurred through GPER1 and its main target gene CTGF, whereas the insulin-induced expression of GPER1 boosted cell-cycle progression and the glucose uptake stimulated by estrogens. Notably, a positive correlation between insulin serum levels and GPER1 expression was found in cancer fibroblasts obtained from breast cancer patients. Altogether, our data indicate that GPER1 may be included among the complex network of transduction signaling triggered by insulin that drives cells toward cancer progression.
authors.affiliation: Department of PharmacyHealth and Nutritional Sciences, University of Calabria, 87036 Rende (CS), ItalyRegional HospitalCosenza, ItalyEndocrinologyDepartment of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: De Marco
authors.affiliation: Department of PharmacyHealth and Nutritional Sciences, University of Calabria, 87036 Rende (CS), ItalyRegional HospitalCosenza, ItalyEndocrinologyDepartment of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Romeo
authors.affiliation: Department of PharmacyHealth and Nutritional Sciences, University of Calabria, 87036 Rende (CS), ItalyRegional HospitalCosenza, ItalyEndocrinologyDepartment of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: Vivacqua
authors.affiliation: Department of PharmacyHealth and Nutritional Sciences, University of Calabria, 87036 Rende (CS), ItalyRegional HospitalCosenza, ItalyEndocrinologyDepartment of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Malaguarnera
authors.affiliation: Department of PharmacyHealth and Nutritional Sciences, University of Calabria, 87036 Rende (CS), ItalyRegional HospitalCosenza, ItalyEndocrinologyDepartment of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Abonante
authors.affiliation: Department of PharmacyHealth and Nutritional Sciences, University of Calabria, 87036 Rende (CS), ItalyRegional HospitalCosenza, ItalyEndocrinologyDepartment of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Romeo
authors.affiliation: Department of PharmacyHealth and Nutritional Sciences, University of Calabria, 87036 Rende (CS), ItalyRegional HospitalCosenza, ItalyEndocrinologyDepartment of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Pezzi
authors.affiliation: Department of PharmacyHealth and Nutritional Sciences, University of Calabria, 87036 Rende (CS), ItalyRegional HospitalCosenza, ItalyEndocrinologyDepartment of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Belfiore
authors.affiliation: Department of PharmacyHealth and Nutritional Sciences, University of Calabria, 87036 Rende (CS), ItalyRegional HospitalCosenza, ItalyEndocrinologyDepartment of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy marcellomaggiolini@yahoo.it.
authors.forename: Marcello
authors.initials: M
authors.lastname: Maggiolini
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C109584:GPER1 protein, human; C532507:GPER1 protein, mouse; D007328:Insulin; D016760:Proto-Oncogene Proteins c-fos; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D018808:Transcription Factor AP-1; D005947:Glucose
keywords: GPER1; cancer cells; cancer-associated fibroblasts (CAFs); estrogen; insulin