Hyperglycemia regulates the glucose-transport system of clonal choriocarcinoma cellsin vitro. A potential molecular mechanism contributing to the adjunct effect of glucose in tumor therapy

Hahn, Tom; Barth, S.; Hofmann, Wolfgang; Reich, Olaf; Lang, Ingrid; Desoyé, Gernot

doi:10.1002/(sici)1097-0215(19981029)78:3<353::aid-ijc16>3.0.co;2-7

Cited by 45 publications

(24 citation statements)

References 21 publications

(19 reference statements)

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“…We speculated that this down-regulation could represent a mechanism to protect fetal development in maternal diabetes. After hyperglycaemia there was, however, no kinetic evidence for a change in the intrinsic activity of the transporters neither in placental trophoblast [11] nor in trophoblast-derived choriocarcinoma cells [13]. The rather moderate extent of GLUT1 protein regulation alone was not sufficient to explain the considerable changes in net glucose uptake measured in these studies.…”

mentioning

confidence: 58%

Hyperglycaemia-induced subcellular redistribution of GLUT1 glucose transporters in cultured human term placental trophoblast cells

Hahn

Blaschitz

et al. 2000

Diabetologia

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confidence: 58%

Hyperglycaemia-induced subcellular redistribution of GLUT1 glucose transporters in cultured human term placental trophoblast cells

Hahn

Blaschitz

et al. 2000

Diabetologia

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“…These cells, thus, offer the unique possibility of identifying biological responses that vary with the degree of trophoblast differentiation. This is exemplified by recent studies from our laboratory in which a hyperglycaemia-induced up-regulation of the GLUT-1 system in JAR was observed but no change in JEG-3 cells [20]. So far BeWo cells have not been investigated.…”

Section: Discussionmentioning

confidence: 98%

“…Proteins of adherent cells were subject to SDS-polyacrylamide gel electrophoresis and immunoblotting as described [20]. The blotting membranes were incubated (60 min, room temperature) with anti-cyclin B1 (1:250; Pharmingen, San Diego) and antip21WAF1 (1:25 or 1:50; Oncogene, Cambridge, Mass., USA) antibodies.…”

Section: Methodsmentioning

confidence: 99%

Hyperglycaemia in vitro alters the proliferation and mitochondrial activity of the choriocarcinoma cell lines BeWo, JAR and JEG-3 as models for human first-trimester trophoblast

Weiß¹,

Červar²,

Puerstner³

et al. 2001

Diabetologia

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Despite considerable advances in the treatment of diabetes in the past decades, diabetic pregnancies can still be associated with fetal growth disturbances even when an optimized and intensive metabolic control has been achieved. Macrosomia of the fetus is a common and well-known consequence of maternal diabetes with an increased obstetric risk. The increase in fetal fat mass that accounts for the fetal overweight [1] is the result of fetal hyperinsulinism as a consequence of maternal and, therefore, fetal hyperglycaemia [2]. According to the dynamics of fetal growth, macrosomia is caused by metabolic alterations or hyperglycaemic insults predominantly in later stages of pregnancy [3,4]. In contrast diabetes-associated metabolic derangements in the first trimester of pregnancy can lead to malformations [5] and to delayed growth of the developing embryo [6,7]. Whereas the molecular mechanisms underlying embryo malformations have received enormous attention, no data are available to explain early fetal growth delay. Because of the close link between placental and fetal growth, early intrauterine growth delay could be caused by a reduced growth of the pla- Diabetologia (2001) Abstract Aims/hypothesis. Early intrauterine growth delay in diabetes could be caused by a reduced growth of the placenta. Our study investigates whether hyperglycaemia in vitro reduces trophoblast proliferation. Methods. First-trimester trophoblast cell models (BeWo, JAR and JEG-3 choriocarcinoma cells) were cultured for 24 and 48 h with 5.5 mmol/l d-glucose, 25 mmol/l d-glucose (hyperglycaemia) and with an osmotic control. Cell number, total protein and nucleic acid content and mitochondrial activity (tetrazolium salt assay) were measured, the cell cycle analysed (FACS, cyclin B1 levels) and apoptosis (Annexin-V) measured.Results. In BeWo cells hyperglycaemia reduced cell number, protein, nucleic acid and cyclin B1 levels. The reduced G 2 /M and increased G 0 /G 1 population after 24 h reflects growth arrest at G 0 /G 1 . In JAR cells after 24 h the population was arrested in G 0 /G 1 , whereas after 48 h the G 0 /G 1 block was abrogated and the cells were arrested at G 2 /M. The net effect was an unchanged cell number. In JEG-3 cells hyperglycaemia resulted in fewer cells after 24 h but not after 48 h indicating some adaptation. Mitochondrial activity was either stimulated (BeWo) or reduced (JAR, JEG-3) under hyperglycaemia. Some of these effects were also induced by hyperosmolarity alone. Conclusion/interpretation. Hyperglycaemia has the potential to inhibit the proliferation of first-trimester trophoblast cell models. The mechanisms leading to growth arrest and to changes in mitochondrial activity are complex and depend on differentiation. We hypothesise a hyperglycaemia-induced impairment of placental growth in the first trimester of a poorly controlled diabetic pregnancy. [Diabetologia (2001) 44: 209±219]

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“…Such a discrepancy between GLUT3 gene expression and protein level could suggest disturbances of the translational process. Because of its high substrate affinity, GLUT3 is the transporter isoform characteristic of cells with high glucose requirements such as neurons or tumor cells (Hahn et al 1998). The K m value of GLUT3 is so small that it may be saturated even at hypoglycemic levels.…”

Section: Discussionmentioning

confidence: 99%

Maternal undernutrition during late gestation-induced intrauterine growth restriction in the rat is associated with impaired placental GLUT3 expression, but does not correlate with endogenous corticosterone levels

Lésage¹,

Hahn²,

Léonhardt³

et al. 2002

Journal of Endocrinology

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Fetal intrauterine growth restriction (IUGR) is a frequently occurring and serious complication of pregnancy. Infants exposed to IUGR are at risk for numerous perinatal morbidities, including hypoglycemia in the neonatal period, as well as increased risk of later physical and/or mental impairments, cardiovascular disease and non-insulin-dependent diabetes mellitus. Fetal growth restriction most often results from uteroplacental dysfunction during the later stage of pregnancy. As glucose, which is the most abundant nutrient crossing the placenta, fulfills a large portion of the fetal energy requirements during gestational development, and since impaired placental glucose transport is thought to result in growth restriction, we investigated the effects of maternal 50% food restriction (FR50) during the last week of gestation on rat placental expression of glucose transporters, GLUT1, GLUT3 and GLUT4, and on plasma glucose content in both maternal and fetal compartments. Moreover, as maternal FR50 induces fetal overexposure to glucocorticoids and since these hormones are potent regulators of placental glucose transporter expression, we investigated whether putative alterations in placental GLUT expression correlate with changes in maternal and/or fetal corticosterone levels.At term (day 21 of pregnancy), plasma glucose content was significantly reduced (P<0·05) in mothers subjected to FR50, but was not affected in fetuses. Food restriction reduced maternal body weight (P<0·001) but did not affect placental weight. Plasma corticosterone concentration, at term, was increased (P<0·05) in FR50 mothers. Fetuses from FR50 mothers showed reduced body weight (P<0·001) but higher plasma corticosterone levels (P<0·05). Adrenalectomy (ADX) followed by corticosterone supplementation of the mother prevented the FR50-induced rise in maternal plasma corticosterone at term. Food restriction performed on either sham-ADX or ADX mothers induced a similar reduction in the body weight of the pups at term (P<0·01). Moreover, plasma corticosterone levels were increased in pups from sham-ADX FR50 mothers (P<0·01) and in pups from ADX control mothers (P<0·01). Western blot analysis of placental GLUT proteins showed that maternal FR50 decreased placental GLUT3 protein levels in all experimental groups at term (P<0·05 and P<0·01), but did not affect either GLUT1 or GLUT4 protein levels. Northern blot analysis of placental GLUT expression showed that both GLUT1 and GLUT3 mRNA were not affected by the maternal feeding regimen or surgery.We concluded that prolonged maternal malnutrition during late gestation decreases maternal plasma glucose content and placental GLUT3 glucose transporter expression, but does not obviously affect fetal plasma glucose concentration. Moreover, the present results are not compatible with a role of maternal corticosterone in the development of growth-restricted rat fetuses.

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Hyperglycemia regulates the glucose-transport system of clonal choriocarcinoma cellsin vitro. A potential molecular mechanism contributing to the adjunct effect of glucose in tumor therapy

Cited by 45 publications

References 21 publications

Hyperglycaemia-induced subcellular redistribution of GLUT1 glucose transporters in cultured human term placental trophoblast cells

Hyperglycaemia-induced subcellular redistribution of GLUT1 glucose transporters in cultured human term placental trophoblast cells

Hyperglycaemia in vitro alters the proliferation and mitochondrial activity of the choriocarcinoma cell lines BeWo, JAR and JEG-3 as models for human first-trimester trophoblast

Maternal undernutrition during late gestation-induced intrauterine growth restriction in the rat is associated with impaired placental GLUT3 expression, but does not correlate with endogenous corticosterone levels

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