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 3H-deoxy-D-glucose (3H-DG; 10 nM) was time-dependent, saturable, inhibited by cytochalasin B (50 and 100 μM), phloretin (0.5 μM) and phloridzin (1 μM), 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 μM), nicotine (100 μM), cocaine (25 μM), amphetamine (10-25 μM) and 3,4-methylenedioxy- N-methamphetamine (10 μM) affected 3H-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 3H-DG uptake, behaving as a non-competitive inhibitor of 3H-DG uptake, both after short- and long-term (24 h) treatment. The effect of XH(5 μM; 24 h) upon 3H-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 lowextracellular 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.