Identification of genes regulated by 2-methoxyestradiol (2ME2) in multiple myeloma cells using oligonucleotide arrays.
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.
Chauhan
Dharminder
D
The Jerome Lipper Multiple Myeloma Center, the Department of Medical Oncology, Cancer Biology, Boston Veteran Affairs Healthcare System, Boston, MA, USA.
Li
Guilan
G
Auclair
Daniel
D
Hideshima
Teru
T
Richardson
Paul
P
Podar
Klaus
K
Mitsiades
Nicholas
N
Mitsiades
Constantine
C
Li
Cheng
C
Kim
Ryung Suk
RS
Munshi
Nikhil
N
Chen
Lan Bo
LB
Wong
Wing
W
Anderson
Kenneth C
KC
D000077584:2-Methoxyestradiol; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017930:Genes, Reporter; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000378:metabolism; D009101:Multiple Myeloma / Q000473:pathology*; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D046988:Proteasome Endopeptidase Complex; D017510:Protein Folding; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D013382:Subtraction Technique; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D015850:Interleukin-6; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D025801:Ubiquitin; D004958:Estradiol; D000077584:2-Methoxyestradiol; D003907:Dexamethasone; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex