title: Glucocorticoid-induced alterations in mitochondrial membrane properties and respiration in childhood acute lymphoblastic leukemia.
abstract: Mitochondria are signal-integrating organelles involved in cell death induction. Mitochondrial alterations and reduction in energy metabolism have been previously reported in the context of glucocorticoid (GC)-triggered apoptosis, although the mechanism is not yet clarified. We analyzed mitochondrial function in a GC-sensitive precursor B-cell acute lymphoblastic leukemia (ALL) model as well as in GC-sensitive and GC-resistant T-ALL model systems. Respiratory activity was preserved in intact GC-sensitive cells up to 24h under treatment with 100 nM dexamethasone before depression of mitochondrial respiration occurred. Severe repression of mitochondrial respiratory function was observed after permeabilization of the cell membrane and provision of exogenous substrates. Several mitochondrial metabolite and protein transporters and two subunits of the ATP synthase were downregulated in the T-ALL and in the precursor B-ALL model at the gene expression level under dexamethasone treatment. These data could partly be confirmed in ALL lymphoblasts from patients, dependent on the molecular abnormality in the ALL cells. GC-resistant cell lines did not show any of these defects after dexamethasone treatment. In conclusion, in GC-sensitive ALL cells, dexamethasone induces changes in membrane properties that together with the reduced expression of mitochondrial transporters of substrates and proteins may lead to repressed mitochondrial respiratory activity and lower ATP levels that contribute to GC-induced apoptosis.
authors.affiliation: Institute of Functional Genomics, University of Regensburg, Josef-Engert-Str. 9, 93053 Regensburg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Eberhart
authors.forename: Johannes
authors.initials: J
authors.lastname: Rainer
authors.forename: Daniel
authors.initials: D
authors.lastname: Bindreither
authors.forename: Ireen
authors.initials: I
authors.lastname: Ritter
authors.forename: Erich
authors.initials: E
authors.lastname: Gnaiger
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kofler
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oefner
authors.forename: Kathrin
authors.initials: K
authors.lastname: Renner
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000494:pharmacology; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D005938:Glucocorticoids / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D046228:Microarray Analysis; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051336:Mitochondrial Membranes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D005938:Glucocorticoids; D003907:Dexamethasone