Dexamethasone-induced apoptotic mechanisms in myeloma cells investigated by analysis of mutant glucocorticoid receptors
- 15 August 2008
- journal article
- Published by American Society of Hematology in Blood
- Vol. 112 (4), 1338-1345
- https://doi.org/10.1182/blood-2007-11-124156
Abstract
The mechanism by which the glucocorticoid (GC) dexamethasone induces apoptosis in multiple myeloma (MM) cells is unknown, although previous work suggests that either transactivation through the glucocorticoid response element (GRE), transrepression of NF-κB, phosphorylation of RAFTK (Pyk2), or induction of Bim is important. We studied this question by ectopically expressing mutant glucocorticoid receptors (GRs) in the dexamethasone-resistant MM1R cell line, which has lost its GR. Lentiviral-mediated reexpression of wild-type GR restored GRE transactivation, NF-κB transrepression, RAFTK phosphorylation, Bim induction, and dexamethasone-induced apoptosis. We then reexpressed 4 GR mutants, each possessing various molecular effects, into MM1R cells. A perfect correlation was present between induction of GRE transactivation and induction of apoptosis. In contrast, NF-κB transrepression and RAFTK phosphorylation were not required for apoptosis. Although not required for dexamethasone-mediated apoptosis, NF-κB inhibition achieved by gene transfer suggested that NF-κB transrepression could contribute to apoptosis in dexamethasone-treated cells. Dexamethasone treatment of MM1R cells expressing a mutant incapable of inducing apoptosis successfully resulted in RAFTK (Pyk2) phosphorylation and Bim induction indicating the latter GR-mediated events were not sufficient to induce apoptosis. MM1R cells expressing mutant GRs will be helpful in defining the molecular mechanisms of dexamethasone-induced apoptosis of myeloma cells.This publication has 33 references indexed in Scilit:
- Frequent Engagement of the Classical and Alternative NF-κB Pathways by Diverse Genetic Abnormalities in Multiple MyelomaCancer Cell, 2007
- Promiscuous Mutations Activate the Noncanonical NF-κB Pathway in Multiple MyelomaCancer Cell, 2007
- Glucocorticoid receptor transcriptional isoforms and resistance in multiple myeloma cellsMolecular Cancer Therapeutics, 2006
- MLN120B, a Novel IκB Kinase β Inhibitor, Blocks Multiple Myeloma Cell Growth In vitro and In vivoClinical Cancer Research, 2006
- Dexamethasone resistance in B-cell precursor childhood acute lymphoblastic leukemia occurs downstream of ligand-induced nuclear translocation of the glucocorticoid receptorBlood, 2005
- The imbalance between Bim and Mcl‐1 expression controls the survival of human myeloma cellsEuropean Journal of Immunology, 2004
- Downregulation of Bim, a Proapoptotic Relative of Bcl-2, Is a Pivotal Step in Cytokine-Initiated Survival Signaling in Murine Hematopoietic ProgenitorsMolecular and Cellular Biology, 2001
- SHP2 Mediates the Protective Effect of Interleukin-6 against Dexamethasone-induced Apoptosis in Multiple Myeloma CellsOnline Journal of Public Health Informatics, 2000
- RAFTK/PYK2-dependent and -independent apoptosis in multiple myeloma cellsOncogene, 1999
- Expression and Subcellular Distribution of the -Isoform of the Human Glucocorticoid ReceptorEndocrinology, 1997