title: Xanthohumol impairs glucose uptake by a human first-trimester extravillous trophoblast cell line (HTR-8/SVneo cells) and impacts the process of placentation.
abstract: In this study, we aimed to investigate modulation of glucose uptake by the HTR-8/SVneo human first-trimester extravillous trophoblast cell line by a series of compounds and to study its consequences upon cell proliferation, viability and migration. We observed that uptake of (3)H-deoxy-d-glucose ((3)H-DG; 10 nM) was time-dependent, saturable, inhibited by cytochalasin B (50 and 100 µM), phloretin (0.5 mM) and phloridzin (1 mM), insulin-insensitive and sodium-independent. In the short term (30 min), neither 5-HT (100-1000 µM), melatonin (10 nM) nor the drugs of abuse ethanol (100 mM), nicotine (100 µM), cocaine (25 µM), amphetamine (10-25 µM) and 3,4-methylenedioxy-N-methamphetamine (10 µM) affected (3)H-DG uptake, while dexamethasone (100-1000 µM), fluoxetine (100-300 µM), quercetin, epigallocatechin-3-gallate (30-1000 µM), xanthohumol (XH) and resveratrol (1-500 µM) decreased it. XH was the most potent inhibitor [IC50 = 3.55 (1.37-9.20) µM] of (3)H-DG uptake, behaving as a non-competitive inhibitor of (3)H-DG uptake, both after short- and long-term (24 h) treatment. The effect of XH (5 µM; 24 h) upon (3)H-DG uptake involved mammalian target of rapamycin, tyrosine kinases and c-Jun N-terminal kinases intracellular pathways. Moreover, XH appeared to decrease cellular uptake of lactate due to inhibition of the monocarboxylate transporter 1. Additionally, XH (24 h; 5 µM) decreased cell viability, proliferation, culture growth and migration. The effects of XH upon cell viability and culture growth, but not the antimigratory effect, were mimicked by low extracellular glucose conditions and reversed by high extracellular glucose conditions. We thus suggest that XH, by inhibiting glucose cellular uptake and impairing HTR-8/SVneo cell viability and proliferation, may have a deleterious impact in the process of placentation.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Correia-Branco
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: Cláudia F
authors.initials: CF
authors.lastname: Azevedo
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal Institute Pasteur, INSERM U786, Unity of Molecular Microbial Pathogenesis, Paris 75015, France.
authors.forename: João R
authors.initials: JR
authors.lastname: Araújo
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal Department of Clinical Pathology, São João Hospital Center, Porto 4200-319, Portugal.
authors.forename: João T
authors.initials: JT
authors.lastname: Guimarães
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal Chemistry Investigation Centre (CIQ), Faculty of Sciences, University of Porto, Porto, Portugal Faculty of Nutrition and Food Sciences, University of Porto, Porto 4200-465, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Faria
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal Centre of Biotechnology and Fine Chemistry, School of Biotechnology, Portuguese Catholic University, Porto, Portugal.
authors.forename: Elisa
authors.initials: E
authors.lastname: Keating
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal fmartel@med.up.pt.
authors.forename: Fátima
authors.initials: F
authors.lastname: Martel
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects; D003571:Cytochalasin B / Q000494:pharmacology / Q000633:toxicity; D003847:Deoxyglucose / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D005419:Flavonoids / Q000494:pharmacology* / Q000633:toxicity; D005947:Glucose / Q000494:pharmacology; D051246:Glucose Transport Proteins, Facilitative / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D013287:Illicit Drugs / Q000494:pharmacology / Q000633:toxicity; D008550:Melatonin / Q000494:pharmacology / Q000633:toxicity; D010693:Phloretin / Q000494:pharmacology / Q000633:toxicity; D010695:Phlorhizin / Q000494:pharmacology / Q000633:toxicity; D010929:Placentation / Q000187:drug effects*; D059808:Polyphenols / Q000494:pharmacology / Q000633:toxicity; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011427:Propiophenones / Q000494:pharmacology* / Q000633:toxicity; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology / Q000633:toxicity; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects*
chemical_list: D005419:Flavonoids; D051246:Glucose Transport Proteins, Facilitative; D013287:Illicit Drugs; D059808:Polyphenols; D011427:Propiophenones; D013267:Stilbenes; D003571:Cytochalasin B; D003907:Dexamethasone; D003847:Deoxyglucose; D010695:Phlorhizin; C546842:MTOR protein, human; D011505:Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; D008550:Melatonin; D000077185:Resveratrol; D010693:Phloretin; C104536:xanthohumol
keywords: glucose uptake; proliferation; trophoblast cells; viability; xanthohumol