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Transcriptomic profiling of taxol-resistant ovarian cancer cells identifies FKBP5 and the androgen receptor as critical markers of chemotherapeutic response.

ABSTRACT: Taxol is a mitotoxin widely used to treat human cancers, including of the breast and ovary. However, taxol resistance (txr) limits treatment efficacy in human patients. To study chemoresistance in ovarian cancer, we established txr ovarian carcinoma cells derived from the SKOV3 cell lineage. The cells obtained were cross-resistant to other mitotoxins such as vincristine while they showed no resistance to the genotoxin cisplatin. Transcriptomic analysis identified 112 highly up-regulated genes in txr cells. Surprisingly, FK506-binding protein 5 (FKBP5) was transiently up-regulated 100-fold in txr cells but showed decreased expression in prolonged culture. Silencing of FKBP5 sensitized txr cells to taxol, whereas ectopic expression of FKBP5 increased resistance to the drug. Modulation of FKBP5 expression produced similar effects in response to vincristine but not to cisplatin. We observed that a panel of newly identified txr genes was trancriptionally regulated by FKBP5 and silencing of these genes sensitized cells to taxol. Notably, immunoprecipitation experiments revealed that FKBP5 forms a protein complex with the androgen receptor (AR), and this complex regulates the transcriptional activity of both proteins. Furthermore, we found that the Akt kinase pathway is regulated by FKBP5. These results indicate that the FKBP5/AR complex may affect cancer cell sensitivity to taxol by regulating expression of txr genes. Our findings suggest that mitotoxin-based treatment against ovarian cancer should be avoided when the Akt/FKBP5/AR axis is activated.

SUBMITTER: Sun NK

PROVIDER: S-EPMC4322968 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Transcriptomic profiling of taxol-resistant ovarian cancer cells identifies FKBP5 and the androgen receptor as critical markers of chemotherapeutic response.

Sun Nian-Kang NK Huang Shang-Lang SL Chang Pu-Yuan PY Lu Hsing-Pang HP Chao Chuck C-K CC

Oncotarget 20141201 23

Taxol is a mitotoxin widely used to treat human cancers, including of the breast and ovary. However, taxol resistance (txr) limits treatment efficacy in human patients. To study chemoresistance in ovarian cancer, we established txr ovarian carcinoma cells derived from the SKOV3 cell lineage. The cells obtained were cross-resistant to other mitotoxins such as vincristine while they showed no resistance to the genotoxin cisplatin. Transcriptomic analysis identified 112 highly up-regulated genes in ...[more]

PMID: 25460502

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Project description:BackgroundOvarian cancer is a significant cancer-related cause of death in women worldwide. The most used chemotherapeutic regimen is based on carboplatin (CBDCA). However, CBDCA resistance is the main obstacle to a better prognosis. An in vitro drug-resistant cell model would help in the understanding of molecular mechanisms underlying this drug-resistance phenomenon. The aim of this study was to characterize cellular and molecular changes of induced CBDCA-resistant ovarian cancer cell line A2780.MethodsThe cell selection strategy used in this study was a dose-per-pulse method using a concentration of 100 μM for 2 h. Once 20 cycles of exposure to the drug were completed, the cell cultures showed a resistant phenotype. Then, the ovarian cancer cell line A2780 was grown with 100 μM of CBDCA (CBDCA-resistant cells) or without CBDCA (parental cells). After, a drug sensitivity assay, morphological analyses, cell death assays and a RNA-seq analysis were performed in CBDCA-resistant A2780 cells.ResultsMicroscopy on both parental and CBDCA-resistant A2780 cells showed similar characteristics in morphology and F-actin distribution within cells. In cell-death assays, parental A2780 cells showed a significant increase in phosphatidylserine translocation and caspase-3/7 cleavage compared to CBDCA-resistant A2780 cells (P < 0.05 and P < 0.005, respectively). Cell viability in parental A2780 cells was significantly decreased compared to CBDCA-resistant A2780 cells (P < 0.0005). The RNA-seq analysis showed 156 differentially expressed genes (DEGs) associated mainly to molecular functions.ConclusionCBDCA-resistant A2780 ovarian cancer cells is a reliable model of CBDCA resistance that shows several DEGs involved in molecular functions such as transmembrane activity, protein binding to cell surface receptor and catalytic activity. Also, we found that the Wnt/β-catenin and integrin signaling pathway are the main metabolic pathway dysregulated in CBDCA-resistant A2780 cells.

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Dataset Information

Transcriptomic profiling of taxol-resistant ovarian cancer cells identifies FKBP5 and the androgen receptor as critical markers of chemotherapeutic response.

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Transcriptomic profiling of taxol-resistant ovarian cancer cells identifies FKBP5 and the androgen receptor as critical markers of chemotherapeutic response.

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