Metabolic Modeling Identifies Key Control Points in Carbohydrate Metabolism in Uterine Cancer Cell Line (Ishikawa)

Additional Funding Sources

The project described was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grant No. P20GM103408.

Abstract

Endometrial cancer is one of the most common gynecological cancers. Tumors are well-known to depend on ATP synthesis via glycolysis. Both estrogen and progesterone play a role in regulating endometrial cell growth, however, the way these hormones regulate glycolysis kinetically is not yet understood. We adapted a kinetic computational model that could identify flux controlling steps of glycolysis because these steps would be therapeutic targets for uterine cancer chemotherapy. Ishikawa cells, human endometrial adenocarcinoma cells that express progesterone and estradiol receptors, were treated with vehicle (DMSO), 50 nM estradiol, or 10 uM progesterone for 24 hrs at 5 mM glucose before measuring glycolysis, glycogen metabolism, or enzyme activities. All rates and concentrations were normalized to protein by a BCA assay. A computational model built in COPASI was adapted with all enzyme parameters and measured fluxes in order to determine the distribution of flux control. Glycolysis was significantly upregulated by estrogen, though glucose uptake was not affected by hormones. Several glycolytic enzymes were downregulated by E2 and only a few P4 affected only a few Kms. HK, PFK, and HPI had the highest flux control and are therefore may be good targets or therapeutic targets for uterine cancer.

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Metabolic Modeling Identifies Key Control Points in Carbohydrate Metabolism in Uterine Cancer Cell Line (Ishikawa)

Endometrial cancer is one of the most common gynecological cancers. Tumors are well-known to depend on ATP synthesis via glycolysis. Both estrogen and progesterone play a role in regulating endometrial cell growth, however, the way these hormones regulate glycolysis kinetically is not yet understood. We adapted a kinetic computational model that could identify flux controlling steps of glycolysis because these steps would be therapeutic targets for uterine cancer chemotherapy. Ishikawa cells, human endometrial adenocarcinoma cells that express progesterone and estradiol receptors, were treated with vehicle (DMSO), 50 nM estradiol, or 10 uM progesterone for 24 hrs at 5 mM glucose before measuring glycolysis, glycogen metabolism, or enzyme activities. All rates and concentrations were normalized to protein by a BCA assay. A computational model built in COPASI was adapted with all enzyme parameters and measured fluxes in order to determine the distribution of flux control. Glycolysis was significantly upregulated by estrogen, though glucose uptake was not affected by hormones. Several glycolytic enzymes were downregulated by E2 and only a few P4 affected only a few Kms. HK, PFK, and HPI had the highest flux control and are therefore may be good targets or therapeutic targets for uterine cancer.