title: G protein-coupled estrogen receptor mediates the up-regulation of fatty acid synthase induced by 17β-estradiol in cancer cells and cancer-associated fibroblasts.
abstract: Activation of lipid metabolism is an early event in carcinogenesis and a central hallmark of many tumors. Fatty acid synthase (FASN) is a key lipogenic enzyme catalyzing the terminal steps in the de novo biogenesis of fatty acids. In cancer cells, FASN may act as a metabolic oncogene, given that it confers growth and survival advantages to these cells, whereas its inhibition effectively and selectively kills tumor cells. Hormones such as estrogens and growth factors contribute to the transcriptional regulation of FASN expression also through the activation of downstream signaling and a cross-talk among diverse transduction pathways. In this study, we demonstrate for the first time that 17β-estradiol (E2) and the selective GPER ligand G-1 regulate FASN expression and activity through the GPER-mediated signaling, which involved the EGF receptor/ERK/c-Fos/AP1 transduction pathway, as ascertained by using specific pharmacological inhibitors, performing gene-silencing experiments and ChIP assays in breast SkBr3, colorectal LoVo, hepatocarcinoma HepG2 cancer cells, and breast cancer-associated fibroblasts. In addition, the proliferative effects induced by E2 and G-1 in these cells involved FASN as the inhibitor of its activity, named cerulenin, abolished the growth response to both ligands. Our data suggest that GPER may be included among the transduction mediators involved by estrogens in regulating FASN expression and activity in cancer cells and cancer-associated fibroblasts that strongly contribute to cancer progression.
authors.affiliation: Department of Pharmaco-Biology, University of Calabria, 87030 Rende, Italy.
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Santolla
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Lappano
authors.forename: Paola
authors.initials: P
authors.lastname: De Marco
authors.forename: Marco
authors.initials: M
authors.lastname: Pupo
authors.forename: Adele
authors.initials: A
authors.lastname: Vivacqua
authors.forename: Diego
authors.initials: D
authors.lastname: Sisci
authors.forename: Sergio
authors.initials: S
authors.lastname: Abonante
authors.forename: Domenico
authors.initials: D
authors.lastname: Iacopetta
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Cappello
authors.forename: Vincenza
authors.initials: V
authors.lastname: Dolce
authors.forename: Marcello
authors.initials: M
authors.lastname: Maggiolini
mesh_terms: D002569:Cerulenin / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D054872:Fatty Acid Synthesis Inhibitors / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D004967:Estrogens; D054872:Fatty Acid Synthesis Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D043562:Receptors, G-Protein-Coupled; D018808:Transcription Factor AP-1; D002569:Cerulenin; D004958:Estradiol; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; C512478:EGFR protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases