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1.
J Steroid Biochem Mol Biol ; 126(3-5): 104-12, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21569845

ABSTRACT

The ability of inhibitors of transcription and translation to prevent glucocorticoid-induced apoptosis has been interpreted to indicate that the cell death machinery requires de novo protein synthesis. The transcriptional inhibitors actinomycin D (Act D) and DRB as well as the translational inhibitors CHX and puromycin inhibited early loss of mitochondrial membrane integrity in a dose-dependent manner. This effect was not observed with the transcriptional inhibitor α-amanitin suggesting they may have additional effects. Their role in the glucocorticoid receptor (GR) intracellular trafficking was therefore investigated. Here, we show that Act D and CHX reduced glucocorticoid binding, GR turnover and impaired GR nuclear translocation. We performed the same experiments in different thymocyte subpopulations of Balb/c mice. At the highest dose tested, actinomycin D and cycloheximide abolished glucocorticoid-induced cell death of CD4+CD8+ and CD4+CD8-. In all subsets, Act D, DRB, as well as CHX and puromycin prevented receptor nuclear translocation, indicating a general alteration of GR trafficking. Overall, our data support a direct effect of macromolecular inhibitors on GR activation and trafficking. Finally, direct alterations of the functional properties of the glucocorticoid receptor might be responsible for cell death prevention by actinomycin D, DRB, cycloheximide and puromycin.


Subject(s)
Nucleic Acid Synthesis Inhibitors/pharmacology , Protein Synthesis Inhibitors/pharmacology , Receptors, Glucocorticoid/metabolism , Alpha-Amanitin/pharmacology , Animals , Cells, Cultured , Cycloheximide/pharmacology , Dactinomycin/pharmacology , Glucocorticoids/metabolism , HeLa Cells , Humans , Macromolecular Substances/antagonists & inhibitors , Macromolecular Substances/metabolism , Mice , Mice, Inbred BALB C , Protein Binding , Protein Transport/drug effects , Puromycin/pharmacology , Thymus Gland/cytology , Thymus Gland/drug effects , Thymus Gland/metabolism
2.
Biochim Biophys Acta ; 1593(2-3): 277-82, 2003 Feb 17.
Article in English | MEDLINE | ID: mdl-12581872

ABSTRACT

The synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN/CD437) appears to possess an apoptotic activity superior to classical retinoids in vitro as in vivo. Numerous studies have shown that CD437-induced apoptosis is independent of its nuclear receptor activity, suggesting that CD437 might have a unique mechanism of action. The purpose of this study was to compare CD437- and all-trans retinoic acid (atRA)-induced cell death. CD437 provoked a rapid apoptotic phenotype immediately followed by secondary necrosis in RPMI 8226, U266 and L363 human myeloma cell lines. Nuclear apoptotic features were observed upon both CD437 and atRA treatments. In contrast, membrane blebbing and the subsequent formation of apoptotic bodies, a classical apoptotic event, was only observed upon atRA treatment. In addition, CD437, contrary to atRA, was unable to induce tissue transglutaminase (tTG), an intracellular enzyme involved in the formation of cross-linked protein polymers contributing to apoptotic morphological changes. Taken together, these data suggest that CD437 induces rapid but incomplete apoptotic phenotype in human myeloma cells.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis , Retinoids/pharmacology , Tumor Cells, Cultured/drug effects , Cell Survival/drug effects , Fluorescent Antibody Technique, Indirect , Humans , Lamin Type B/analysis , Multiple Myeloma , RNA, Messenger , Transglutaminases/analysis , Tretinoin/pharmacology , Tumor Cells, Cultured/diagnostic imaging , Tumor Cells, Cultured/enzymology , Ultrasonography
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