TY - JOUR
T1 - Identification of genes regulated by 2-methoxyestradiol (2ME2) in multiple myeloma cells using oligonucleotide arrays
AU - Chauhan, Dharminder
AU - Li, Guilan
AU - Auclair, Daniel
AU - Hideshima, Teru
AU - Richardson, Paul
AU - Podar, Klaus
AU - Mitsiades, Nicholas
AU - Mitsiades, Constantine
AU - Li, Cheng
AU - Kim, Ryung Suk
AU - Munshi, Nikhil
AU - Chen, Lan Bo
AU - Wong, Wing
AU - Anderson, Kenneth C
PY - 2003/5/1
Y1 - 2003/5/1
N2 - Our previous study demonstrated that 2-methoxyestradiol (2ME2), an estrogen derivative, induces apoptosis in multiple myeloma (MM) cells; however, the related transcriptional events are unclear. In the present study, we used oligonucleotide microarrays to identify genes altered during 2ME2-induced apoptosis in MM cells. 2ME2 triggers an early transient induction of genes known to trigger cell death and repression of growth/survival-related genes. Many genes regulating cell defense/repair machinery also were transiently induced. Since 2ME2 also induces apoptosis in MM cells resistant to conventional therapies such as dexamethasone (Dex), we compared the gene profiles of 2ME2-treated and Dex-resistant MM cells. Our results suggest that 2ME2 overcomes Dex resistance by modulating genes that confer chemoresistance in MM cells. Microarray results were confirmed by Northern and Western blot analyses. A comparative analysis of selected genes from freshly isolated MM patient cells and 2ME2-treated MM.1S MM cells further provides an in vivo relevance of our in vitro studies. Collectively, these findings suggest genetic events mediating anti-MM activity of 2ME2, as well as mechanisms whereby 2ME2 overcomes Dex resistance in MM cells. These studies may therefore allow improved therapeutic use of 2ME2, based upon targeting genes that regulate MM cell growth and survival.
AB - Our previous study demonstrated that 2-methoxyestradiol (2ME2), an estrogen derivative, induces apoptosis in multiple myeloma (MM) cells; however, the related transcriptional events are unclear. In the present study, we used oligonucleotide microarrays to identify genes altered during 2ME2-induced apoptosis in MM cells. 2ME2 triggers an early transient induction of genes known to trigger cell death and repression of growth/survival-related genes. Many genes regulating cell defense/repair machinery also were transiently induced. Since 2ME2 also induces apoptosis in MM cells resistant to conventional therapies such as dexamethasone (Dex), we compared the gene profiles of 2ME2-treated and Dex-resistant MM cells. Our results suggest that 2ME2 overcomes Dex resistance by modulating genes that confer chemoresistance in MM cells. Microarray results were confirmed by Northern and Western blot analyses. A comparative analysis of selected genes from freshly isolated MM patient cells and 2ME2-treated MM.1S MM cells further provides an in vivo relevance of our in vitro studies. Collectively, these findings suggest genetic events mediating anti-MM activity of 2ME2, as well as mechanisms whereby 2ME2 overcomes Dex resistance in MM cells. These studies may therefore allow improved therapeutic use of 2ME2, based upon targeting genes that regulate MM cell growth and survival.
KW - 2-Methoxyestradiol
KW - Cell Cycle Proteins/biosynthesis
KW - Cysteine Endopeptidases/metabolism
KW - Cytoskeletal Proteins/biosynthesis
KW - DNA-Binding Proteins/biosynthesis
KW - Dexamethasone/pharmacology
KW - Drug Resistance, Neoplasm
KW - Endoplasmic Reticulum/metabolism
KW - Estradiol/analogs & derivatives
KW - Gene Expression Profiling
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Genes, Reporter
KW - Heat-Shock Proteins/biosynthesis
KW - Interleukin-6/pharmacology
KW - Multienzyme Complexes/metabolism
KW - Multiple Myeloma/pathology
KW - Neoplasm Proteins/biosynthesis
KW - Oligonucleotide Array Sequence Analysis
KW - Proteasome Endopeptidase Complex
KW - Protein Folding
KW - RNA, Messenger/biosynthesis
KW - RNA, Neoplasm/biosynthesis
KW - Regulatory Factor X Transcription Factors
KW - Subtraction Technique
KW - Transcription Factors/biosynthesis
KW - Transfection
KW - Tumor Cells, Cultured/drug effects
KW - Ubiquitin/metabolism
UR - http://www.scopus.com/inward/record.url?scp=0038542892&partnerID=8YFLogxK
U2 - 10.1182/blood-2002-10-3146
DO - 10.1182/blood-2002-10-3146
M3 - Journal article
C2 - 12480690
SN - 0006-4971
VL - 101
SP - 3606
EP - 3614
JO - Blood
JF - Blood
IS - 9
ER -