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Characterisation and manipulation of docetaxel resistant prostate cancer cell lines.

ABSTRACT: There is no effective treatment strategy for advanced castration-resistant prostate cancer. Although Docetaxel (Taxotere®) represents the most active chemotherapeutic agent it only gives a modest survival advantage with most patients eventually progressing because of inherent or acquired drug resistance. The aims of this study were to further investigate the mechanisms of resistance to Docetaxel. Three Docetaxel resistant sub-lines were generated and confirmed to be resistant to the apoptotic and anti-proliferative effects of increasing concentrations of Docetaxel.The resistant DU-145 R and 22RV1 R had expression of P-glycoprotein and its inhibition with Elacridar partially and totally reversed the resistant phenotype in the two cell lines respectively, which was not seen in the PC-3 resistant sublines. Resistance was also not mediated in the PC-3 cells by cellular senescence or autophagy but multiple changes in pro- and anti-apoptotic genes and proteins were demonstrated. Even though there were lower basal levels of NF-?B activity in the PC-3 D12 cells compared to the Parental PC-3, docetaxel induced higher NF-?B activity and I?B phosphorylation at 3 and 6 hours with only minor changes in the DU-145 cells. Inhibition of NF-?B with the BAY 11-7082 inhibitor reversed the resistance to Docetaxel.This study confirms that multiple mechanisms contribute to Docetaxel resistance and the central transcription factor NF-?B plays an immensely important role in determining docetaxel-resistance which may represent an appropriate therapeutic target.

SUBMITTER: O'Neill AJ

PROVIDER: S-EPMC3203088 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Characterisation and manipulation of docetaxel resistant prostate cancer cell lines.

O'Neill Amanda J AJ Prencipe Maria M Dowling Catherine C Fan Yue Y Mulrane Laoighse L Gallagher William M WM O'Connor Darran D O'Connor Robert R Devery Aoife A Corcoran Claire C Rani Sweta S O'Driscoll Lorraine L Fitzpatrick John M JM Watson R William G RW

Molecular cancer 20111007

<h4>Background</h4>There is no effective treatment strategy for advanced castration-resistant prostate cancer. Although Docetaxel (Taxotere®) represents the most active chemotherapeutic agent it only gives a modest survival advantage with most patients eventually progressing because of inherent or acquired drug resistance. The aims of this study were to further investigate the mechanisms of resistance to Docetaxel. Three Docetaxel resistant sub-lines were generated and confirmed to be resistant ...[more]

PMID: 21982118

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Project description:BackgroundProstate cancer is a broad-spectrum disease, spanning from indolent to a highly aggressive lethal malignancy. Prostate cancer cell lines are essential tools to understanding the basic features of this malignancy, as well as in identifying novel therapeutic strategies. However, most cell lines routinely used in prostate cancer research are derived from metastatic disease and may not fully elucidate the molecular events underlying the early stages of cancer development and progression. Thus, there is a need for new cell lines derived from localised disease to better span the disease spectrum.MethodsProstatic tissue from the primary site, and adjacent non-cancerous tissue was obtained from four patients with localised disease undergoing radical prostatectomy. Epithelial cell outgrowths were immortalised with human papillomavirus type 16 (HPV16) E6 and E7 to establish monoclonal cell lines. Chromosomal ploidy was imaged and STR profiles were determined. Cell morphology, colony formation and cell proliferation characteristics were assessed. Androgen receptor (AR) expression and AR-responsiveness to androgen treatment were analysed by immunofluorescence and RT-qPCR, respectively. RNA-seq analysis was performed to identify prostate lineage markers and expression of prostate cancer tumorigenesis-related genes.ResultsTwo benign cell lines derived from non-cancer cells (AQ0420 and AQ0396) and two tumour tissue derived cancer cell lines (AQ0411 and AQ0415) were immortalised from four patients with localised prostatic adenocarcinoma. The cell lines presented an epithelial morphology and a slow to moderate proliferative rate. None of the cell lines formed anchorage independent colonies or displayed AR-responsiveness. Comparative RNA-seq expression analysis confirmed the prostatic lineage of the four cell lines, with a distinct gene expression profile from that of the metastatic prostate cancer cell lines, PC-3 and LNCaP.ConclusionsComprehensive characterization of these cell lines may provide new in vitro tools that could bridge the current knowledge gap between benign, early-stage and metastatic disease.

Dataset Information

Characterisation and manipulation of docetaxel resistant prostate cancer cell lines.

Publications

Characterisation and manipulation of docetaxel resistant prostate cancer cell lines.

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