Transcriptomics,Genomics

Dataset Information

49

Beta-microseminoprotein (MSMB) downregulation is associated with increased drug resistance in ovarian cancer


ABSTRACT: Resistance to current chemotherapeutic agents is major cause of therapy failure in ovarian cancer patients. To better understand mechanisms of drug resistance, and possibly identify novel targets for therapy, we generated a series of ovarian cancer cell lines that are resistant to various chemotherapeutic drugs (cisplatin, doxorubicin, and paclitaxel), and identified key resistance genes and pathways using whole-genome expression analysis. Our data identify a number of genes altered in the drug resistant lines compared to drug-sensitive cells, and further validation finds an interesting candidate MSMB to be consistently decreased at both the mRNA and protein levels in all the drug-resistant ovarian cancer cells. Through knockdown and overexpression experiments in cell culture models, we show that MSMB has a functional role in drug resistance. Using a mouse xenograft model, we show that re-expression of MSMB in drug-resistant cells can partially reverse the drug resistant phenotype. MSMB-expressing cells have increased caspase-3 activity and known downstream targets, including the PAK2-MLCK-actin pathway, are found activated, providing a possible molecular mechanism for the roles of MSMB in drug resistance. Thus, our study identifies a novel gene in ovarian cancer drug resistance and elucidates a portion of the signaling pathway that may be crucial in its function. Our data suggest a new mechanism for the development of drug resistance in ovarian cancer and identify possible new targets for therapy. Overall design: To study the mechanisms involved in the development of resistance to anti-cancer agents, the drug-sensitive OV90 ovarian cancer cell line was used to generate a series of cell lines, each individually resistant to different drugs. Repeated cycles of drug exposure followed by recovery periods led to the development drug resistance in these cells. Using this approach, we generated OV90 sublines resistant to cisplatin, doxorubicin and paclitaxel. The lines resistant to cisplatin (OV90C-A, OV90C-D), doxorubicin (OV90D-6, OV90D-7) and paclitaxel (OV90P-3, OV90P-7) all exhibited significant resistance to their corresponding drugs compared to the parental OV90 cell. Cross resistance was also investigated and we found that the cisplatin resistant lines (OV90C-A and OV90C-D) were not cross-resistant to doxorubicin or paclitaxel. In contrast, the doxorubicin resistant cells (OV90D-6 and OV90D-7) were cross-resistant to paclitaxel, and the paclitaxel resistant cells (OV90P-3 and OV90P-7) were also resistant to both cisplatin and doxorubicin. To identify genes and pathways important in the development of drug resistance, we performed gene expression profiling analysis on the OV90 drug sensitive cell line and on the resistant cell lines using Illumina Sentrix microarrays. For each of the resistance types (cisplatin, doxorubicin, and paclitaxel) two independent sublines were profiled in duplicate (two different cultures). Multidimensional scaling (MDS) analysis based on the genes expression data showed that the cell lines were grouped according to their resistance phenotype, demonstrating that the selection for resistance to different drugs led to overall different patterns of gene expression changes. This suggested different mechanisms of resistance for the different drugs.

INSTRUMENT(S): Illumina humanRef-8 v2.0 expression beadchip

SUBMITTER: Kevin G Becker  

PROVIDER: GSE26465 | GEO | 2012-03-12

SECONDARY ACCESSION(S): PRJNA136537

REPOSITORIES: GEO

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Publications

Gene expression and pathway analysis of ovarian cancer cells selected for resistance to cisplatin, paclitaxel, or doxorubicin.

Sherman-Baust Cheryl A CA   Becker Kevin G KG   Wood Iii William H WH   Zhang Yongqing Y   Morin Patrice J PJ  

Journal of ovarian research 20111205 1


BACKGROUND: Resistance to current chemotherapeutic agents is a major cause of therapy failure in ovarian cancer patients, but the exact mechanisms leading to the development of drug resistance remain unclear. METHODS: To better understand mechanisms of drug resistance, and possibly identify novel targets for therapy, we generated a series of drug resistant ovarian cancer cell lines through repeated exposure to three chemotherapeutic drugs (cisplatin, doxorubicin, or paclitaxel), and identified c  ...[more]

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