title: Insulin-like growth factor-I regulates GPER expression and function in cancer cells.
abstract: Functional cross talk between insulin-like growth factor-I (IGF-I) system and estrogen signaling has been largely reported, although the underlying molecular mechanisms remain to be fully elucidated. As GPR30/GPER mediates rapid cell responses to estrogens, we evaluated the potential of IGF-I to regulate GPER expression and function in estrogen receptor (ER)α-positive breast (MCF-7) and endometrial (Ishikawa) cancer cells. We found that IGF-I transactivates the GPER promoter sequence and upregulates GPER mRNA and protein levels in both cells types. Similar data were found, at least in part, in carcinoma-associated fibroblasts. The upregulation of GPER expression by IGF-I involved the IGF-IR/PKCδ/ERK/c-fos/AP1 transduction pathway and required ERα, as ascertained by specific pharmacological inhibitors and gene-silencing. In both MCF-7 and Ishikawa cancer cells, the IGF-I-dependent cell migration required GPER and its main target gene CTGF, whereas the IGF-I-induced proliferation required both GPER and cyclin D1. Our data demonstrate that the IGF-I system regulates GPER expression and function, triggering the activation of a signaling network that leads to the migration and proliferation of cancer cells.
authors.affiliation: Department of Pharmaco-Biology, University of Calabria, Rende, Italy.
authors.forename: P
authors.initials: P
authors.lastname: De Marco
authors.forename: V
authors.initials: V
authors.lastname: Bartella
authors.forename: A
authors.initials: A
authors.lastname: Vivacqua
authors.forename: R
authors.initials: R
authors.lastname: Lappano
authors.forename: M F
authors.initials: MF
authors.lastname: Santolla
authors.forename: A
authors.initials: A
authors.lastname: Morcavallo
authors.forename: V
authors.initials: V
authors.lastname: Pezzi
authors.forename: A
authors.initials: A
authors.lastname: Belfiore
authors.forename: M
authors.initials: M
authors.lastname: Maggiolini
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D016889:Endometrial Neoplasms / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D047628:Estrogen Receptor alpha; C109584:GPER1 protein, human; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D007334:Insulin-Like Growth Factor I