Role of protein kinase A in regulating steroid sulfate uptake for estrogen production in human placental choriocarcinoma cells

Tomi, Masatoshi; Miyata, Yosuke; Noguchi, Saki; Nishimura, S.; Nishimura, Tomohiro; Nakashima, Emi

doi:10.1016/j.placenta.2014.06.003

Cited by 8 publications

(10 citation statements)

References 24 publications

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“…The secretion of estrogen from JEG-3 cells was observed when precursor sulfoconjugated steroids were added to cells (33) and was increased by protein kinase A activation (34), which plays a key role in the differentiation of cytotrophoblasts into syncytiotrophoblasts. We recently reported that protein kinase A activation by forskolin up-regulates OAT4 in JEG-3 cells (16). Accordingly, OAT4 in cytotrophoblasts would be also involved in the 16␣-OH DHEAS uptake and contribute to estriol synthesis, but the activity of estriol synthesis is expected to be up-regulated in syncytiotrophoblasts through the differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…JEG-3 cells were treated with 100 M forskolin (Sigma) for 72 hours prior to the experiment to stimulate biochemical and morphological differentiation of cytotrophoblast-like choriocarcinoma cells into syncytiotrophoblast-like cells, which show increased expression of OAT4 (16). Cell viability was measured in terms of reduced nicotinamide adenine dinucleotide (phosphate)-dependent oxidoreductase activity [microculture tetrazolium (MTT) assay] using a CellTiter 96 nonradioactive cell proliferation assay kit (Promega).…”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

“…Choriocarcinoma JEG-3 cells are biochemically and morphologically differentiated into syncytiotrophoblast-like cells by forskolin, and forskolin-differentiated JEG-3 cells possess functional activity of OAT4 (16). [ 3 H]16␣-OH DHEAS uptake activity was observed in for- skolin-differentiated JEG-3 cells ( Figure 4A).…”

Section: Effect Of Oat4 Inhibitor On Estriol Secretion In Choriocarcimentioning

confidence: 99%

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Role of OAT4 in Uptake of Estriol Precursor 16α-Hydroxydehydroepiandrosterone Sulfate Into Human Placental Syncytiotrophoblasts From Fetus

et al. 2015

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Estriol biosynthesis in human placenta requires the uptake of a fetal liver-derived estriol precursor, 16α-hydroxydehydroepiandrosterone sulfate (16α-OH DHEAS), by placental syncytiotrophoblasts at their basal plasma membrane (BM), which faces the fetal circulation. The aim of this work is to identify the transporter(s) mediating 16α-OH DHEAS uptake at the fetal side of syncytiotrophoblasts by using human placental BM-enriched vesicles and to examine the contribution of the putative transporter to estriol synthesis at the cellular level, using choriocarcinoma JEG-3 cells. Organic anion transporter (OAT)-4 and organic anion transporting polypeptide 2B1 proteins were enriched in human placental BM vesicles compared with crude membrane fraction. Uptake of [(3)H]16α-OH DHEAS by BM vesicles was partially inhibited in the absence of sodium but was significantly increased in the absence of chloride and after preloading glutarate. Uptake of [(3)H]16α-OH DHEAS by BM vesicles was significantly inhibited by OAT4 substrates such as dehydroepiandrosterone sulfate, estrone-3-sulfate, and bromosulfophthalein but not by cyclosporin A, tetraethylammonium, p-aminohippuric acid, or cimetidine. These characteristics of vesicular [(3)H]16α-OH DHEAS uptake are in good agreement with those of human OAT4-transfected COS-7 cells as well as forskolin-differentiated JEG-3 cells. Estriol secretion from differentiated JEG-3 cells was detected when the cells were incubated with 16α-OH DHEAS for 8 hours but was inhibited in the presence of 50 μM bromosulfophthalein. Our results indicate that OAT4 at the BM of human placental syncytiotrophoblasts plays a predominant role in the uptake of 16α-OH DHEAS for placental estriol synthesis.

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Section: Discussionmentioning

confidence: 99%

Section: Cell Culture and Transfectionmentioning

confidence: 99%

Section: Effect Of Oat4 Inhibitor On Estriol Secretion In Choriocarcimentioning

confidence: 99%

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Role of OAT4 in Uptake of Estriol Precursor 16α-Hydroxydehydroepiandrosterone Sulfate Into Human Placental Syncytiotrophoblasts From Fetus

et al. 2015

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“…Organic anion transporter 4 at the BM of syncytiotrophoblasts is thought to take part in estrogen synthesis by taking up precursor steroid sulfates such as DHEAS and 16"OH-DHEAS from the fetal circulation 13,32 and also protects the fetus from the toxicity of these steroid sulfates. 23,33 Olmesartan efflux via OAT4 was facilitated by extracellular DHEAS at more than 1 :M (Fig.…”

Section: Discussionmentioning

confidence: 99%

Organic Anion Transporter 4-Mediated Transport of Olmesartan at Basal Plasma Membrane of Human Placental Barrier

Noguchi

Nishimura

Fujibayashi

et al. 2015

Journal of Pharmaceutical Sciences

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Mechanisms regulating fetal transfer of olmesartan, an angiotensin-II receptor type 1 antagonist, are important as potential determinants of life-threatening adverse fetal effects. The purpose of this study was to examine the olmesartan transport mechanism through the basal plasma membrane (BM) of human syncytiotrophoblasts forming the placental barrier. Uptake of olmesartan by human placental BM vesicles was potently inhibited by dehydroepiandrosterone sulfate (DHEAS), estrone 3-sulfate, and bromosulfophthalein, which are all typical substrates of organic anion transporter (OAT) 4 localized at the BM of syncytiotrophoblasts, and was increased in the absence of chloride. In tetracycline-inducible OAT4-expressing cells, [(3) H]olmesartan uptake was increased by tetracycline treatment. Olmesartan uptake via OAT4 was concentration dependent with a Km of 20 μM, and was increased in the absence of chloride. [(3) H]Olmesartan efflux via OAT4 was also observed and was trans-stimulated by extracellular chloride and DHEAS. Thus, OAT4 mediates bidirectional transport of olmesartan and appears to regulate fetal transfer of olmesartan at the BM of syncytiotrophoblasts. Efflux transport of olmesartan via OAT4 from syncytiotrophoblasts to the fetal circulation might be facilitated in the presence of an inwardly directed physiological chloride gradient and extracellular DHEAS.

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“…Syncytin-1 is expressed in placental syncytiotrophoblasts and is involved in the fusion of cytotrophoblast cells to form the multinucleated syncytial layer of the placenta. An increased expression of syncytin-1 was observed in syncytiotrophoblast-like differentiating JEG-3 cells [16]. Furthermore, the differentiation pattern of JEG-3 cultured in CS-C medium (Cell Systems, USA) resembled the syncytiotrophoblastlike differentiation signal in vivo [17].…”

Section: Expression Of Mrna For Syncytin-1 In Jeg-3 Cells In Several mentioning

confidence: 97%

Molecular and functional characterization of choline transporter in the human trophoblastic cell line JEG-3 cells

et al. 2015

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Role of protein kinase A in regulating steroid sulfate uptake for estrogen production in human placental choriocarcinoma cells

Cited by 8 publications

References 24 publications

Role of OAT4 in Uptake of Estriol Precursor 16α-Hydroxydehydroepiandrosterone Sulfate Into Human Placental Syncytiotrophoblasts From Fetus

Role of OAT4 in Uptake of Estriol Precursor 16α-Hydroxydehydroepiandrosterone Sulfate Into Human Placental Syncytiotrophoblasts From Fetus

Organic Anion Transporter 4-Mediated Transport of Olmesartan at Basal Plasma Membrane of Human Placental Barrier

Molecular and functional characterization of choline transporter in the human trophoblastic cell line JEG-3 cells

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