Abstract
11β-hydroxysteroid dehydrogenases type 2 (11β-HSD2), a key regulator for pre-receptor metabolism of glucocorticoids (GCs) by converting active GC, cortisol, to inactive cortisone, has been shown to be present in a variety of tumors. But its expression and roles have rarely been discussed in hematological malignancies. Proteasome inhibitor bortezomib has been shown to not only possess antitumor effects but also potentiate the activity of other chemotherapeutics. In this study, we demonstrated that 11β-HSD2 was highly expressed in two GC-resistant T-cell leukemic cell lines Jurkat and Molt4. In contrast, no 11β-HSD2 expression was found in two GC-sensitive non-hodgkin lymphoma cell lines Daudi and Raji as well as normal peripheral blood T cells. Inhibition of 11β-HSD2 by 11β-HSD inhibitor 18β-glycyrrhetinic acid or 11β-HSD2 shRNA significantly increased cortisol-induced apoptosis in Jurkat cells. Additionally, pretreatment of Jurkat cells with low-dose bortezomib resulted in increased cellular sensitivity to GC as shown by elevated induction of apoptosis, more cells arrested at G1 stage and up-regulation of GC-induced leucine zipper which is an important mediator of GC action. Furthermore, we clarified that bortezomib could dose-dependently inhibit 11β-HSD2 messenger RNA and protein levels as well as activity (cortisol-cortisone conversion) through p38 mitogen-activated protein kinase signaling pathway. Therefore, we suggest 11β-HSD2 is, at least partially if not all, responsible for impaired GC suppression in Jurkat cells and also indicate a novel mechanism by which proteasome inhibitor bortezomib may influence GC action.
Highlights
Glucocorticoids (GCs), stress hormones secreted from the adrenal gland, are physiologically involved in metabolism, cell differentiation, and several aspects of the maintenance of homeostasis
We reported 11bHSD2 presence was partly responsible for GC resistance in leukemia T cells and bortezomib enhanced GC sensitivity in Jurkat cells by P38 mitogen-activated protein kinase (MAPK)mediated down-regulation of 11b-HSD2, suggesting that 11bHSD2 could be used as a potential therapeutic target in GCresistant lymphoproliferative disorders and a novel downstream target of bortezomib action
A deficient up-regulation of the glucocorticoid receptor (GR) and its downstream target, GC-induced leucine zipper (GILZ) was found in GCresistant subclones generated from a GC-sensitive cell line, which was attributed to mutational events [3]
Summary
Glucocorticoids (GCs), stress hormones secreted from the adrenal gland, are physiologically involved in metabolism, cell differentiation, and several aspects of the maintenance of homeostasis. They play their parts by combining with cognate intracellular glucocorticoid receptor (GR) and translocating to the nucleus afterwards [1]. In childhood acute lymphoblastic leukaemia (ALL) treatment protocols, an introductory monotherapy GC has been used to reduce leukemic blasts in GC sensitive patients in the initial therapy. GC sensitivity is different from person to person and GC-resistance is a therapeutic problem with an unclear molecular mechanism. Some studies have suggested that the GC receptor is underexpressed or mutated in GC-resistant cells, but others have reached contradictory results [3,4,5], indicating the possibility of multiple diverse mechanisms involved in GC resistance
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