Transcriptomics

Dataset Information

7

The investigational Aurora kinase A inhibitor MLN8237 induces defects in cell viability and cell cycle progression in mouse bladder cancer cells in vitro and in vivo


ABSTRACT: PURPOSE: Despite over 70,000 new cases of bladder cancer in the United States annually, patients with advanced disease have a poor prognosis due to limited treatment modalities. We evaluate the role of Aurora A, identified as an upregulated candidate molecule in bladder cancer, in regulating bladder tumor growth. EXPERIMENTAL DESIGN: Gene expression in human bladder cancer samples was evaluated using RNA microarray and reverse-transcriptase PCR. The specific Aurora kinase A inhibitor MLN8237 (Millennium) was used to determine effects on bladder cancer cell growth using in vitro and in vivo models using malignant T24 and UM-UC-3 and papilloma-derived RT4 bladder cells. RESULTS: Urothelial carcinoma upregulates a set of 13 mitotic spindle associated transcripts, as compared to normal urothelium, including MAD2L1 (7.6-fold), BUB1B (8.8-fold), Aurora kinases A (5.6-fold) and Aurora kinase B (6.2-fold). Application of MLN8237 (10nM-1µM) to the human bladder tumor cell lines T24 and UM-UC-3 induced dose-dependent G2 cell cycle arrest, aneuploidy, mitotic spindle abnormalities, and apoptosis. MLN8237 arrested tumor growth when administered orally over 4 weeks in a mouse bladder cancer xenograft model (p<0.05). Finally, in vitro combination of MLN8237 with either paclitaxel or gemcitabine produced schedule-dependent synergistic antiproliferative effects in T24 cells when administered sequentially. CONCLUSIONS: Mitotic spindle checkpoint dysfunction is a common characteristic of human urothelial carcinoma, and can be exploited with pharmacologic Aurora A inhibition. Future studies that explore the mechanisms of spindle checkpoint failure in bladder cancer and evaluate the therapeutic role of Aurora kinases for bladder cancer patients would be of value. Tissue samples with urothelial cell carcinoma from bladder as well as normal references were collected and the gene expression profiles were compared. No technical replicates.

ORGANISM(S): Homo sapiens  

SUBMITTER: Jacob Zhang   Zhongfa Zhang  Hansel Donna  Bin T The 

PROVIDER: E-GEOD-42089 | ArrayExpress | 2013-05-01

SECONDARY ACCESSION(S): GSE42089PRJNA179103

REPOSITORIES: GEO, ArrayExpress

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Publications

The investigational Aurora kinase A inhibitor MLN8237 induces defects in cell viability and cell-cycle progression in malignant bladder cancer cells in vitro and in vivo.

Zhou Ning N   Singh Kamini K   Mir Maria C MC   Parker Yvonne Y   Lindner Daniel D   Dreicer Robert R   Ecsedy Jeffrey A JA   Zhang Zhongfa Z   Teh Bin T BT   Almasan Alexandru A   Hansel Donna E DE  

Clinical cancer research : an official journal of the American Association for Cancer Research 20130212 7


Despite more than 70,000 new cases of bladder cancer in the United States annually, patients with advanced disease have a poor prognosis due to limited treatment modalities. We evaluated Aurora kinase A, identified as an upregulated candidate molecule in bladder cancer, as a potential therapeutic target.Gene expression in human bladder cancer samples was evaluated using RNA microarray and quantitative reverse transcriptase PCR. Effects of the Aurora kinase A inhibitor MLN8237 (Millennium) on cel  ...[more]

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