title: Inhibitory effect of fluvoxamine on β-casein expression via a serotonin-independent mechanism in human mammary epithelial cells.
abstract: Selective serotonin reuptake inhibitors (SSRIs) are widely used as a first-line therapy in postpartum depression. The objective of this study was to determine the mechanism underlying the inhibitory effects of the SSRI, fluvoxamine, on β-casein expression, an indicator of lactation, in MCF-12A human mammary epithelial cells. Expression levels of serotonin (5-hydroxytryptamine; 5-HT) transporter, an SSRI target protein, and tryptophan hydroxylase 1, a rate-limiting enzyme in 5-HT biosynthesis, were increased in MCF-12A cells by prolactin treatment. Treatment with 1 μM fluvoxamine for 72 h significantly decreased protein levels of β-casein and phosphorylated signal transducer and activator transcription 5 (pSTAT5). Extracellular 5-HT levels were significantly increased after exposure to 1 μM fluvoxamine, in comparison with those of untreated and vehicle-treated cells; however, extracellular 5-HT had little effect on the decrease in β-casein expression. Expression of glucose-related protein 78/binding immunoglobulin protein, a regulator of endoplasmic reticulum (ER) stress, was significantly increased after treatment with 1 μM fluvoxamine for 48 h. Exposure to tunicamycin, an inducer of ER stress, also decreased expression of β-casein and pSTAT5 in a manner similar to fluvoxamine. Our results indicate that fluvoxamine suppresses β-casein expression in MCF-12A cells via inhibition of STAT5 phosphorylation caused by induction of ER stress. Further studies are required to confirm the effect of fluvoxamine on the function of mammary epithelial cells.
authors.affiliation: Department of Clinical Pharmaceutics and Pharmacy Practice, School of Pharmacy, Iwate Medical University, 2-1-1, Nishitokuta, Yahabacho, Shiwagun, Iwate 028-3603, Japan. Electronic address: chibat@iwate-med.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Chiba
authors.affiliation: Department of Pharmacology, Nihon Pharmaceutical University, 10281 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan.
authors.forename: Tomoji
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Department of Hospital Pharmacy, Faculty of Pharmaceutical Sciences, Josai University, 1-1, Keyakidai, Sakadoshi, Saitama 350-0295, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Kimura
authors.affiliation: Department of Hospital Pharmacy, Faculty of Pharmaceutical Sciences, Josai University, 1-1, Keyakidai, Sakadoshi, Saitama 350-0295, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Morimoto
authors.affiliation: Department of Pharmacotherapeutics, School of Pharmacy, Iwate Medical University, 2-1-1, Nishitokuta, Yahabacho, Shiwagun, Iwate 028-3603, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbe
authors.affiliation: Department of Hospital Pharmacy, Faculty of Pharmaceutical Sciences, Josai University, 1-1, Keyakidai, Sakadoshi, Saitama 350-0295, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Ueda
authors.affiliation: Department of Clinical Pharmaceutics and Pharmacy Practice, School of Pharmacy, Iwate Medical University, 2-1-1, Nishitokuta, Yahabacho, Shiwagun, Iwate 028-3603, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Kudo
mesh_terms: D002364:Caseins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D016666:Fluvoxamine / Q000494:pharmacology*; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D002364:Caseins; D016666:Fluvoxamine; D050799:STAT5 Transcription Factor; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Endoplasmic reticulum stress; MCF-12A; Mammary gland; Selective serotonin reuptake inhibitor; Serotonin; β-casein