title: Expression of 11beta-hydroxysteroid dehydrogenase 2 contributes to glucocorticoid resistance in lymphoblastic leukemia cells.
abstract: Synthetic glucocorticoids (GCs) form a crucial first-line treatment for childhood acute lymphoblastic leukemia (ALL). However prolonged GC therapy frequently leads to GC-resistance with an unclear molecular mechanism. 11β-hydroxysteroid dehydrogenase (11β-HSD) 2 inactivates GCs within cells. Here, we show the association between GC sensitivity and 11β-HSD2 expression in human T-cell leukemic cell lines. 11β-HSD2 mRNA and protein levels were considerably higher in GC-resistant MOLT4F cells than in GC-sensitive CCRF-CEM cells. The 11β-HSD inhibitor, carbenoxolone pre-treatment resulted in greater cell death with prednisolone assessed by methyl-thiazol-tetrazolium assay and caspase-3/7 assay, suggesting that 11β-HSD2 is a cause of GC-resistance in ALL.
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan. sshuji@hama-med.ac.jp
authors.forename: Shuji
authors.initials: S
authors.lastname: Sai
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Rie
authors.initials: R
authors.lastname: Yamaguchi
authors.forename: Masako
authors.initials: M
authors.lastname: Suzuki
authors.forename: Kimiyoshi
authors.initials: K
authors.lastname: Sakaguchi
authors.forename: Shuichi
authors.initials: S
authors.lastname: Okada
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
authors.forename: Takehiko
authors.initials: T
authors.lastname: Ohzeki
authors.forename: Karen E
authors.initials: KE
authors.lastname: Chapman
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000502:physiology; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D011239:Prednisolone / Q000008:administration & dosage / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; D003907:Dexamethasone; D011239:Prednisolone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2