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Quantitative proteomic determination of diethylstilbestrol action on prostate cancer.

ABSTRACT: Diethylstilbestrol (DES) has a direct cellular mechanism inhibition on prostate cancer. Its action is independent from the oestrogen receptors and is preserved after a first-line hormonal therapy. We aimed to identify proteins involved in the direct cellular inhibition effects of DES on prostate cancer. We used a clonogenic assay to establish the median lethal concentration of DES on 22RV1 cells. 22RV1 cells were exposed to standard and DES-enriched medium. After extraction, protein expression levels were obtained by two-dimensional differential in-gel electrophoresis (2D-DIGE) and isotope labelling tags for relative and absolute quantification (iTRAQ). Proteins of interest were analysed by quantitative RT-PCR and western blotting. The differentially regulated proteins (P<0.01) were interrogated against a global molecular network based on the ingenuity knowledge base. The 2D-DIGE analyses revealed DES-induced expression changes for 14 proteins (>1.3 fold; P<0.05). The iTRAQ analyses allowed the identification of 895 proteins. Among these proteins, 65 had a modified expression due to DES exposure (i.e., 23 overexpressed and 42 underexpressed). Most of these proteins were implicated in apoptosis and redox processes and had a predicted mitochondrial expression. Additionally, ingenuity pathway analysis placed the OAT and HSBP1 genes at the centre of a highly significant network. RT-PCR confirmed the overexpression of OAT (P=0.006) and HSPB1 (P=0.046).

SUBMITTER: Bigot P

PROVIDER: S-EPMC3739640 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Quantitative proteomic determination of diethylstilbestrol action on prostate cancer.

Bigot Pierre P Mouzat Kevin K Lebdai Souhil S Bahut Muriel M Benhabiles Nora N Tassin Géraldine Cancel GC Azzouzi Abdel-Rahmène AR Cussenot Olivier O

Asian journal of andrology 20130225 3

Diethylstilbestrol (DES) has a direct cellular mechanism inhibition on prostate cancer. Its action is independent from the oestrogen receptors and is preserved after a first-line hormonal therapy. We aimed to identify proteins involved in the direct cellular inhibition effects of DES on prostate cancer. We used a clonogenic assay to establish the median lethal concentration of DES on 22RV1 cells. 22RV1 cells were exposed to standard and DES-enriched medium. After extraction, protein expression l ...[more]

PMID: 23435471

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Project description:BackgroundProstate cancer (PCa) is the most frequently diagnosed non-skin cancer and a leading cause of mortality among males in developed countries. However, our understanding of the global changes of protein complexes within PCa tissue specimens remains very limited, although it has been well recognized that protein complexes carry out essentially all major processes in living organisms and that their deregulation drives the pathogenesis and progression of various diseases.MethodsBy coupling tandem mass tagging-synchronous precursor selection-mass spectrometry/mass spectrometry/mass spectrometry with differential expression and co-regulation analyses, the present study compared the differences between protein complexes in normal prostate, low-grade PCa, and high-grade PCa tissue specimens.ResultsGlobally, a large downregulated putative protein-protein interaction (PPI) network was detected in both low-grade and high-grade PCa, yet a large upregulated putative PPI network was only detected in high-grade but not low-grade PCa, compared with normal controls. To identify specific protein complexes that are deregulated in PCa, quantified proteins were mapped to protein complexes in CORUM (v3.0), a high-quality collection of 4274 experimentally verified mammalian protein complexes. Differential expression and gene ontology (GO) enrichment analyses suggested that 13 integrin complexes involved in cell adhesion were significantly downregulated in both low- and high-grade PCa compared with normal prostate, and that four Prothymosin alpha (ProTα) complexes were significantly upregulated in high-grade PCa compared with normal prostate. Moreover, differential co-regulation and GO enrichment analyses indicated that the assembly levels of six protein complexes involved in RNA splicing were significantly increased in low-grade PCa, and those of four subcomplexes of mitochondrial complex I were significantly increased in high-grade PCa, compared with normal prostate.ConclusionsIn summary, to the best of our knowledge, the study represents the first large-scale and quantitative, albeit indirect, comparison of individual protein complexes in human PCa tissue specimens. It may serve as a useful resource for better understanding the deregulation of protein complexes in primary PCa.

Project description:The role of further hormone therapy in castration-resistant prostate cancer (CRPC) remains unclear. We performed a multi-centre randomised phase III study comparing the use of Dexamethasone, Aspirin, and immediate addition of Diethylstilbestrol (DAiS) vs Dexamethasone, Aspirin, and deferred (until disease progression) addition of Diethylstilbestrol (DAdS).From 2001 to 2008, 270 men with chemotherapy-naive CRPC were randomly assigned, in a 1 : 1 ratio, to receive either DAiS or DAdS. They were stratified for performance status, presence of bone metastases, and previous normalisation of prostate-specific antigen (PSA) to androgen deprivation. The study end points were the proportion of patients achieving a 50% PSA response, progression-free survival (PFS), overall survival, and quality of life. Intention-to-treat analysis was carried out. The effect of treatment was studied first by Kaplan-Meier curves and log-rank test, and finally through multivariable stratified Cox's proportional hazards model adjusting for the effects of possible baseline prognostic factors. Quality of life was analysed using multivariate analysis of variance.At study entry, the median age was 76 years (inter-quartile range: 70-80 years), the median PSA was 79 ng ml(-1), and 76% of the cohort had metastatic disease. The response rates for DAiS (68%) and DAdS (64%) were not significantly different (P=0.49). Similar to the response rate, neither the PFS (median=8.1 months for both arms) nor the overall survival (19.4 vs 18.8 months) differed significantly between the DAiS and DAdS groups (P>0.20). However, the response rate for the DAiS (68%) was significantly higher than the response rate of DA (before adding Diethylstilbestrol) (50%) (P=0.002). Similarly, the median time to progression for DAiS (8.6 months) was significantly longer than that of DA (4.5 months) (P<0.001). Multivariable analysis showed that patients with previous haemoglobin ≥11 g dl(-1) decreased the risk of death significantly (hazard ratio: 0.44, 95% CI: 0.25-0.77). Patients treated with previous anti-androgens alone had more than 5 times more risk of death compared with patients treated with gonadorelin analogues throughout their castration-sensitive phase. Treatment sequencing did not affect the quality of life but pre-treatment performance status did. The incidence of veno-thromboembolic events was 22% (n=28) in DAiS and 11% (n=14) in the DA arm (P=0.02). Painful gynaecomastia occurred in only 1% on DA, whereas in 40% on DAiS (P=0.001).Dexamethasone and immediate Diethylstilbestrol resulted in neither higher PSA response rate nor higher PFS compared with Dexamethasone with deferred Diethylstilbestrol. There was no suggestion of significantly improved overall survival or quality of life. Given the significantly higher toxicity of Diethylstilbestrol, deferring Diethylstilbestrol until failure of Dexamethasone is the preferred strategy when using these agents in CRPC.

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Quantitative proteomic determination of diethylstilbestrol action on prostate cancer.

Publications

Quantitative proteomic determination of diethylstilbestrol action on prostate cancer.

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