Tumor necrosis factor-alpha related gene response to Epothilone B in ovarian cancer.
OBJECTIVE
Epothilone B (EpoB) is a non-taxane microtubule-stabilizing agent with a mode of action similar to that of paclitaxel, but with the advantage of being active in paclitaxel-resistant cells. Knowledge regarding other mechanisms of EpoB action is limited. The purpose of this study was to identify gene expression profiles associated with the biological response to EpoB in an ovarian cancer cell line (SKOV3).


METHODS
SKOV3 cells were maintained in McCoy's 5A media. Equal densities cells were treated with or without EpoB, and were evaluated for cell growth arrest and apoptosis. mRNA expression was evaluated by cDNA microarrays and quantitative, real time reverse transcription polymerase chain reaction (QRTPCR).


RESULTS
EpoB (10 nM) led to cell cycle arrest and apoptosis in SKOV3 cells. Microarray analysis, comparing EpoB-treated to untreated cells, revealed altered expression of 41 genes. There was a predominance of sequences related to the TNFalpha stress response pathway. Differential expression of selected genes was confirmed by QRTPCR.


CONCLUSIONS
We demonstrated that cDNA microarrays are a useful tool to rapidly screen for patterns of gene expression that characterize drug response. The microarray data suggest that the microtubule-stabilizing agent, EpoB, triggers stress-related signal transduction pathways related to TNFalpha. These pathways may contribute to mechanisms of EpoB action and potential mechanisms of resistance in ovarian cancer.
Khabele
Dineo
D
Albert Einstein Cancer Center and Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA. dkhabele@montefiore.org
Lopez-Jones
Melissa
M
Yang
WanCai
W
Arango
Diego
D
Gross
Susan J
SJ
Augenlicht
Leonard H
LH
Goldberg
Gary L
GL
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D034261:Epothilones / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016195:G2 Phase / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008668:Metallothionein / Q000096:biosynthesis / Q000235:genetics; D008938:Mitosis / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*; D015854:Up-Regulation
D000970:Antineoplastic Agents; D034261:Epothilones; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D008668:Metallothionein; C022616:thiazolyl blue; C093788:epothilone B