Dataset Information

11 beta-hydroxysteroid dehydrogenase type 1 expression in 2S FAZA hepatoma cells is hormonally regulated: a model system for the study of hepatic glucocorticoid metabolism.

ABSTRACT: 11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) is a key enzyme in glucocorticoid metabolism, catalysing the conversion of active glucocorticoids into their inactive 11-keto metabolites, thus regulating glucocorticoid access to intracellular receptors. The type 1 isoform (11 beta-HSD 1) (EC 1.1.1.146) is widely distributed, with particularly high levels in liver, where accumulating evidence suggests that it acts as an 11 beta-reductase, regenerating active glucocorticoids. Investigation of the function and regulation of 11 beta-HSD 1 in liver has been hampered by the lack of hepatic cell lines which express 11 beta-HSD 1. Here, we describe 11 beta-HSD 1 mRNA expression and activity in 2S FAZA cells, a continuously cultured rat liver cell line. In intact 2S FAZA cells 11 beta-HSD 1 acts predominantly as a reductase, with very low dehydrogenase activity. In 2S FAZA cells 11 beta-HSD 1 activity and mRNA expression are regulated by hormones, with dexamethasone increasing activity and insulin, forskolin and insulin-like growth factor 1 decreasing it. Transfection of 2S FAZA cells with a luciferase reporter gene driven by the proximal promoter of the rat 11 beta-HSD 1 gene demonstrates that sequences which can mediate the responses to insulin, dexamethasone and forskolin all lie within 1800 bp of the transcription start site.

SUBMITTER: Voice MW

PROVIDER: S-EPMC1217531 | biostudies-other | 1996 Jul

REPOSITORIES: biostudies-other

ACCESS DATA

Similar Datasets

Project description:BackgroundRecent studies have shown that production of cortisol not only takes place in several non-adrenal peripheral tissues such as epithelial cells but, also, the local inter-conversion between cortisone and cortisol is regulated by the 11?-hydroxysteroid dehydrogenases (11?-HSDs). However, little is known about the activity of this non-adrenal glucocorticoid system in cancers.MethodsThe presence of a functioning glucocorticoid system was assessed in human skin squamous cell carcinoma (SCC) and melanoma and further, in 16 epithelial cell lines from 8 different tissue types using ELISA, western blotting and immunofluorescence. 11?-HSD2 was inhibited both pharmacologically and by siRNA technology. Naïve CD8+ T cells were used to test the paracrine effects of cancer-derived cortisol on the immune system in vitro. Functional assays included cell-cell adhesion and cohesion in two- and three-dimensional models. Immunohistochemical data of 11?-HSD expression were generated using tissue microarrays of 40 cases of human SCCs as well as a database featuring 315 cancer cases from 15 different tissues.ResultsWe show that cortisol production is a common feature of malignant cells and has paracrine functions. Cortisol production correlated with the magnitude of glucocorticoid receptor (GR)-dependent inhibition of tumour-specific CD8+ T cells in vitro. 11?-HSDs were detectable in human skin SCCs and melanoma. Analyses of publicly available protein expression data of 11?-HSDs demonstrated that 11?-HSD1 and -HSD2 were dysregulated in the majority (73%) of malignancies. Pharmacological manipulation of 11?-HSD2 activity by 18?-glycyrrhetinic acid (GA) and silencing by specific siRNAs modulated the bioavailability of cortisol. Cortisol also acted in an autocrine manner and promoted cell invasion in vitro and cell-cell adhesion and cohesion in two- and three-dimensional models. Immunohistochemical analyses using tissue microarrays showed that expression of 11?-HSD2 was significantly reduced in human SCCs of the skin.ConclusionsThe results demonstrate evidence of a cancer-associated glucocorticoid system and show for the first time, the functional significance of cancer-derived cortisol in tumour progression.

Dataset Information

11 beta-hydroxysteroid dehydrogenase type 1 expression in 2S FAZA hepatoma cells is hormonally regulated: a model system for the study of hepatic glucocorticoid metabolism.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets