title: Altered folate metabolism modifies cell proliferation and progesterone secretion in human placental choriocarcinoma JEG-3 cells.
abstract: Folate is an essential B vitamin required for de novo purine and thymidylate synthesis, and for the remethylation of homocysteine to form methionine. Folate deficiency has been associated with placenta-related pregnancy complications, as have SNP in genes of the folate-dependent enzymes, methionine synthase (MTR) and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1). We aimed to determine the effect of altered folate metabolism on placental cell proliferation, viability and invasive capacity and on progesterone and human chorionic gonadotropin (hCG) secretion. Human placental choriocarcinoma (JEG-3) cells cultured in low folic acid (FA) (2 nM) demonstrated 13% (P<0.001) and 26% (P<0.001) lower proliferation, 5.5% (P=0.025) and 7.5% (P=0.004) lower invasion capacity, and 5 to 7.5% (P=0.004-0.025) lower viability compared with control (20 nM) or supplemented (100 nM) cells, respectively. FA concentration had no effect on progesterone or hCG secretion. Small interfering RNA (siRNA) knockdown of MTR gene and protein expression resulted in 17.7% (P<0.0001) lower proliferation and 61% (P=0.014) higher progesterone secretion, but had no effect on cell invasion and hCG secretion. siRNA knockdown of MTHFD1 gene expression in the absence of detectable changes in protein expression resulted in 10.3% (P=0.001) lower cell proliferation, but had no effect on cell invasion and progesterone or hCG secretion. Our data indicate that impaired folate metabolism can result in lower trophoblast proliferation, and could alter viability, invasion capacity and progesterone secretion, which may explain in part the observed associations between folate and placenta-related complications.
authors: 1Nutrition Research Division,Health Canada,Ottawa,ON,CanadaK1A 0K9.
authors: Carolyne
authors: C
authors: Moussa
authors: 1Nutrition Research Division,Health Canada,Ottawa,ON,CanadaK1A 0K9.
authors: Nikia
authors: N
authors: Ross
authors: 1Nutrition Research Division,Health Canada,Ottawa,ON,CanadaK1A 0K9.
authors: Philippe
authors: P
authors: Jolette
authors: 1Nutrition Research Division,Health Canada,Ottawa,ON,CanadaK1A 0K9.
authors: Amanda J
authors: AJ
authors: MacFarlane
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002822:Choriocarcinoma / Q000378:metabolism / Q000473:pathology; D006063:Chorionic Gonadotropin / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D006801:Humans; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015778:Minor Histocompatibility Antigens; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009994:Osmolar Concentration; D010920:Placenta / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D010929:Placentation; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D014594:Uterine Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D006063:Chorionic Gonadotropin; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D011374:Progesterone; D005492:Folic Acid; C539735:MTHFD1 protein, human; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; C585801:MTR protein, human
keywords: BrdU bromodeoxyuridine; FA folic acid; Folate; Folic acid; Human chorionic gonadotropin; MTHFD1 methyleneTHF dehydrogenase 1; MTR methionine synthase; Placenta; Progesterone; THF tetrahydrofolate; dTMP thymidylate; hCG human chorionic gonadotropin; siRNA small interfering RNA