Identification of genes regulated by dexamethasone in multiple myeloma cells using oligonucleotide arrays.
Our previous studies have characterized Dexamethasone (Dex)-induced apoptotic signaling pathways in multiple myeloma (MM) cells; however, related transcriptional events are not fully defined. In the present study, gene expression profiles of Dex-treated MM cells were determined using oligonucleotide arrays. Dex triggers early transient induction of many genes involved in cell defense/repair-machinery. This is followed by induction of genes known to mediate cell death and repression of growth/survival-related genes. The molecular and genetic alterations associated with Dex resistance in MM cells are also unknown. We compared the gene expression profiles of Dex-sensitive and Dex-resistant MM cells and identified a number of genes which may confer Dex-resistance. Finally, gene profiling of freshly isolated MM patient cells validates our in vitro MM cell line data, confirming an in vivo relevance of these studies. Collectively, these findings provide insights into the basic mechanisms of Dex activity against MM, as well as mechanisms of Dex-resistance in MM cells. These studies may therefore allow improved therapeutic uses of Dex, based upon targeting genes that regulate MM cell growth and survival.
Chauhan
Dharminder
D
The Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, MA 02115, USA.
Auclair
Daniel
D
Robinson
Elisabeth K
EK
Hideshima
Teru
T
Li
Guilan
G
Podar
Klaus
K
Gupta
Deepak
D
Richardson
Paul
P
Schlossman
Robert L
RL
Krett
Nancy
N
Chen
Lan Bo
LB
Munshi
Nikhil C
NC
Anderson
Kenneth C
KC
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics; D019947:Receptors, Interleukin-6 / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D006360:Heat-Shock Proteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D019947:Receptors, Interleukin-6; D018125:Receptors, Transforming Growth Factor beta; D025801:Ubiquitin; D003907:Dexamethasone; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex