Differential regulation of glucose transporter expression by estrogen and progesterone in Ishikawa endometrial cancer cells

Abstract

Estrogen replacement therapy and other unopposed estrogen treatments increase the incidence of endometrial abnormalities, including cancer. However, this effect is counteracted by the co-administration of progesterone. In the endometrium, glucose transporter (GLUT) expression and glucose transport are known to fluctuate throughout the menstrual cycle. Here, we determined the effect of estrogen and progesterone on the expression of GLUT1-4 and on the transport of deoxyglucose in Ishikawa endometrial cancer cells. Cells were incubated with estrogen, progesterone or combined estrogen and progesterone for 24 h and the effect on the expression of GLUT1-4 and on deoxyglucose transport was determined. We show that GLUT1 expression is upregulated by estrogen and progesterone individually, but that combined estrogen and progesterone treatment reverses this increase. Hormonal treatments do not affect GLUT2, GLUT3 or GLUT4 expression. Transport studies demonstrate that estrogen increases deoxyglucose transport at Michaelis-Menten constants (K m s) corresponding to GLUT1/4, an effect which disappears when progesterone is added concomitantly. These data demonstrate that different hormonal treatments differentially regulate GLUT expression and glucose transport in this endometrial cancer cell line. This regulation mirrors the role played by estrogen and progesterone on the incidence of cancer in this tissue and suggests that GLUT1 may be utilized by endometrial cancer cells to fuel their demand for increased energy requirement.

Metabolic syndrome, plasma lipid, lipoprotein and glucose levels, and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)

“…In addition, type 2 diabetes, which is characterized by elevated glucose and insulin levels, is associated with increased endometrial cancer risk (Weiderpass et al 2000, Anderson et al 2001. Uterine GLUT expression and glucose transport are differentially regulated by estrogen and progesterone (Medina et al 2004), and thus may be influenced by endogenous hormones and previous or current use of HRT or OCs. This effect might explain the stronger associations between glucose and endometrial cancer risk among never-users compared with previous users in our study.…”

“…Current users of oral contraceptives (OCs) or hormone replacement therapy (HRT) were also excluded, since they are known to modify hormone and lipid levels and lipoprotein composition (Bradley et al 1978, Wallace et al 1979, and may also have effects on glucose levels and blood pressure (Elgee 1970, Medina et al 2004 depending on the dose and potency of the estrogens and progestins used. We further excluded endometrial tumors of known non-epithelial or non-malignant morphology (World Health Organization 2003).…”

Contributions of phosphorylation to regulation of OCTN2 uptake of carnitine are minimal in BeWo cells

“…However, the strong inhibition of carnitine uptake by progesterone without the accompanying impact on ALP activity suggests other effects of this hormone on OCTN2-mediated transport function. Progesterone is an essential steroid for maintenance of pregnancy, and it is involved in the regulation of the glucose transporter GLUT1, the peptide transporter PEPT1, and other enzymes [26][27][28]. Since the inhibition of carnitine uptake by progesterone was seen after only 20 minutes of preincubation, it is not likely that hormonal regulation of OCTN2 is responsible for these observations.…”

Kinetics of transport and phosphorylation of glucose in cancer cells

“…GLUT over-expression has usually been determined as an mRNA or protein increase (Nagamatsu et al, 1996;Rudlowski et al, 2003), which has led to conclude that activity also increases (Nagamatsu et al, 1996), without carrying out the appropriate kinetic analysis. On the other hand, in the few studies where GLUT activity was determined, non-initial rate conditions (lengthy incubations at 378C) and, arguably, non-metabolizable glucose analogues (2-deoxyglucose and 3-O-methylglucose) were used (Christopher et al, 1976;Fung et al, 1986;Sarabia et al, 1992;Levitsky et al, 1994;Zamora-Leó n et al, 1996;Medina et al, 2004;Griguer et al, 2005). As high variability in the K m values for these analogues has been determined even within the same GLUT type, with some being higher than those for glucose (Gould et al, 1991;Liu et al, 2001), the kinetic parameters thus determined are of little use for metabolic control analysis, kinetic modeling, and comparative purposes among the different GLUT types.…”