title: Glucocorticoid-induced apoptosis and glucocorticoid resistance in acute lymphoblastic leukemia.
abstract: Glucocorticoids (GC) induce cell cycle arrest and apoptosis in lymphoid cells, and therefore constitute a central component in the treatment of lymphoid malignancies, particularly childhood acute lymphoblastic leukemia (ALL). In spite of its clinical significance and considerable efforts in many laboratories, however, the molecular basis of GC-induced apoptosis and the clinically important resistance phenomenon remains poorly defined. The anti-leukemic GC effects are critically dependent upon sufficient expression of the GC receptor (GR) throughout the response. In ALL cell lines, this is associated with, and may depend upon, GR autoinduction. In corresponding in vitro models, GC resistance frequently results from mutations in the GR gene and/or deficient regulation of its expression. The downstream components of the pathway, i.e., the GC-regulated genes responsible for cell death induction, have been studied by microarray-based comparative expression profiling, resulting in identification of a considerable number of GC-regulated candidate genes. Their possible function in the death response is, however, still undefined. One model predicts direct regulation of the apoptotic machinery, e.g., components of the "Bcl-2 rheostat", while a complementary hypothesis suggests deleterious GC effects on essential cellular functions, such as metabolism, production of and/or response to oxygen radicals, general transcription/translation, pH and volume control, etc. These regulatory effects may entail cell death, particularly if maintained for sufficient time through GR autoinduction. The latter form of cell death may occur even in the absence of functional apoptotic machinery (e.g., when caspases are blocked), but in this case appears to entail a more necrotic morphology. Taken together, GC may induce different types of cell death through distinct molecular pathways, depending on the cellular context. GC resistance might frequently result from defective GR expression, perhaps the most efficient means to target multiple antileukemic pathways.
authors.affiliation: Division of Molecular Pathophysiology, Biocenter Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Ploner
authors.forename: Stefan
authors.initials: S
authors.lastname: Schmidt
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Presul
authors.forename: Kathrin
authors.initials: K
authors.lastname: Renner
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schröcksnadel
authors.forename: Johannes
authors.initials: J
authors.lastname: Rainer
authors.forename: Stefan
authors.initials: S
authors.lastname: Riml
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kofler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011965:Receptors, Glucocorticoid / Q000235:genetics
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid