title: Niacin activates the G protein estrogen receptor (GPER)-mediated signalling.
abstract: Nicotinic acid, also known as niacin, is the water soluble vitamin B3 used for decades for the treatment of dyslipidemic diseases. Its action is mainly mediated by the G protein-coupled receptor (GPR) 109A; however, certain regulatory effects on lipid levels occur in a GPR109A-independent manner. The amide form of nicotinic acid, named nicotinamide, acts as a vitamin although neither activates the GPR109A nor exhibits the pharmacological properties of nicotinic acid. In the present study, we demonstrate for the first time that nicotinic acid and nicotinamide bind to and activate the GPER-mediated signalling in breast cancer cells and cancer-associated fibroblasts (CAFs). In particular, we show that both molecules are able to promote the up-regulation of well established GPER target genes through the EGFR/ERK transduction pathway. As a biological counterpart, nicotinic acid and nicotinamide induce proliferative and migratory effects in breast cancer cells and CAFs in a GPER-dependent fashion. Moreover, nicotinic acid prevents the up-regulation of ICAM-1 triggered by the pro-inflammatory cytokine TNF-α and stimulates the formation of endothelial tubes through GPER in HUVECs. Together, our findings concerning the agonist activity for GPER displayed by both nicotinic acid and nicotinamide broaden the mechanisms involved in the biological action of these molecules and further support the potential of a ligand to induce different responses mediated in a promiscuous manner by distinct GPCRs.
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Cosenza, Italy.
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Santolla
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Cosenza, Italy.
authors.forename: Ernestina Marianna
authors.initials: EM
authors.lastname: De Francesco
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Cosenza, Italy.
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Lappano
authors.affiliation: U.O.S. Biopolymers and Proteomics, Irccs AOU San Martino, IST-National Institute for Cancer Research, Genova, Italy.
authors.forename: Camillo
authors.initials: C
authors.lastname: Rosano
authors.affiliation: Regional Hospital, Cosenza, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Abonante
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Cosenza, Italy. Electronic address: marcellomaggiolini@yahoo.it.
authors.forename: Marcello
authors.initials: M
authors.lastname: Maggiolini
mesh_terms: D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009525:Niacin / Q000494:pharmacology*; D009536:Niacinamide / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014803:Vitamin B Complex / Q000494:pharmacology
chemical_list: C109584:GPER1 protein, human; C530636:HCAR2 protein, human; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D014803:Vitamin B Complex; D018799:Intercellular Adhesion Molecule-1; D009536:Niacinamide; D009525:Niacin; C512478:EGFR protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Breast cancer cells; Cancer-associated fibroblasts; GPER; Nicotinamide; Nicotinic acid