Expression and Regulation of 11-β Hydroxysteroid Dehydrogenase Type 2 Enzyme Activity in the Glucocorticoid-Sensitive CEM-C7 Human Leukemic Cell Line

Abstract

Glucocorticoids are commonly used in the first-line treatment of hematological malignancies, such as acute lymphoblastic leukemia, due to the ability of these steroids to activate pro-apoptotic pathways in human lymphocytes. The goal of the current study was to examine the gene expression and enzyme activity of the microsomal enzyme, 11-β hydroxysteroid dehydrogenase type 2 (HSD11B2, HSD2), which is responsible for the oxidation of bioactive glucocorticoids to their inert metabolites. Using the glucocorticoid-sensitive human leukemic cell line, CEM-C7, we were able to detect the expression of HSD2 at the level of mRNA (via RT-PCR), protein (via immunohistochemistry and immunoblotting), and enzyme activity (via conversion of tritiated cortisol to cortisone). Furthermore, we observed that HSD2 enzyme activity is down regulated in CEM-C7 cells that were pretreated with the synthetic glucocorticoid, dexamethasone (100 nM, <15 hours), and that this down regulation of enzyme activity is blocked by the administration of the glucocorticoid receptor antagonist, RU-486. Taken collectively, these data raise the possibility that the effectiveness of glucocorticoids in the treatment of human leukemias may be influenced by: (1) the ability of these neoplastic cells to metabolize glucocorticoids via HSD2 and (2) the ability of these steroids to regulate the expression of this key enzyme.

Maternal prenatal stress and placental gene expression of NR3C1 and HSD11B2: The effects of maternal ethnicity

“…NR3C1 is a nuclear receptor which functions both a transcription factor and as a transcription factor regulator (Palma-Gudiel et al, 2015). NR3C1 has been shown to be expressed in placental tissue and although its function is unclear, it has been postulated that it may be an upstream regulator of placental HSD11B2 gene expression (Garbrecht and Schmidt, 2013). Thus an increase in placental NR3C1 gene expression may be a mechanism through which the placenta increases its sensitivity to glucocorticoids and fetal glucocorticoid exposure (Seckl and Holmes, 2007).…”

Reciprocal Regulation of HSD11B1 and HSD11B2 Predicts Glucocorticoid Sensitivity in Childhood Acute Lymphoblastic Leukemia

“…7 There are few data on dexamethasone regulation of HSD11B2 (encoding 11β-HSD2) in childhood ALL, but one report suggests down-regulation in glucocorticoid-sensitive ALL. 8 Moreover, expression of 11β-HSD2 contributes to prednisolone resistance in lymphoblastic leukemia cells. 9,10 Recently, we have shown reciprocal regulation of 11β-HSD1/2 may predict steroid sensitivity in childhood nephrotic syndrome.…”

Drug resistance-related microRNAs in hematological malignancies: Translating basic evidence into therapeutic strategies

“…GCs are fundamental drugs used in the treatment of hematological malignancies including leukemia, lymphoma, and MM [104,105]. GCs mediate their functions via the glucocorticoid receptor (GR) that binds hormone noncovalently but with high affinity, thereby initiating a complex signal transduction pathway that involves multiple transcription factors and signaling molecules, resulting in programmed cell death [106].…”