Niacin activates the G protein estrogen receptor (GPER)-mediated signalling

• Published in: Cellular signalling 2014-07, Vol.26 (7), p.1466-1475
• Main Authors: Santolla, Maria Francesca, De Francesco, Ernestina Marianna, Lappano, Rosamaria, Rosano, Camillo, Abonante, Sergio, Maggiolini, Marcello
• Format: Article
• Language: English
• Subjects: Biological; Breast; Breast cancer cells; Breast Neoplasms; Cancer; Cancer-associated fibroblasts; Cell Line, Tumor; Cell Movement; Cell Proliferation; ErbB Receptors - metabolism; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Gene Expression Regulation, Neoplastic; GPER; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Intercellular Adhesion Molecule-1 - biosynthesis; Models, Molecular; Molecular Docking Simulation; Niacin - pharmacology; Niacinamide - pharmacology; Nicotinamide; Nicotinic acid; Receptors; Receptors, Estrogen - metabolism; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - metabolism; Receptors, Nicotinic - metabolism; RNA Interference; RNA, Small Interfering; Signal Transduction; Signalling; Transcriptional Activation; Tumor Necrosis Factor-alpha - metabolism; Vitamin B Complex - pharmacology; Vitamins
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2014.03.011

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. •Nicotinic acid and nicotinamide bind to and activate GPER signalling.•Nicotinic acid and nicotinamide induce cell proliferation and migration.•Niacin exerts promiscuous activity by via both GPR109A and GPER.