Transcriptional profiling of transurethral resection samples provides insight into molecular mechanisms of hormone refractory prostate cancer

Stoß, Oliver; Werther, Meike; Zielinski, Dirk; Middel, Peter; Jost, N.; Rüschoff, Josef; Henkel, Thomas; Albers, Peter

doi:10.1038/sj.pcan.4501001

Cited by 9 publications

(6 citation statements)

References 16 publications

(16 reference statements)

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“…This study predicted TFs associated with docetaxel-resistance based on transcriptomic data by utilising an innovative bioinformatics approach (CIA) and compared gene expression profiling of the PC3- Ag cells versus the docetaxel resistant cell lines D8 and D12. In line with recent transcriptomic studies by our group and others on castration-resistance [ 6 , 28 – 31 ], analysis of our gene chip data showed gene expression changes in cellular processes relevant to cancer progression. These included cell proliferation, apoptosis, cell growth, survival and senescence and cell death with 375 unique genes differentially expressed between the parental Ag and docetaxel resistant sublines D8 and D12.…”

Section: Discussionsupporting

confidence: 89%

The prognostic utility of the transcription factor SRF in docetaxel-resistant prostate cancer: in-vitro discovery and in-vivo validation

et al. 2017

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BackgroundDocetaxel based therapy is one of the first line chemotherapeutic agents for the treatment of metastatic castrate-resistant prostate cancer. However, one of the major obstacles in the treatment of these patients is docetaxel-resistance. Defining the mechanisms of resistance so as to inform subsequent treatment options and combinations represents a challenge for clinicians and scientists.Previous work by our group has shown complex changes in pro and anti-apoptotic proteins in the development of resistance to docetaxel. Targeting these changes individually does not significantly impact on the resistant phenotype but understanding the central signalling pathways and transcription factors (TFs) which control these could represent a more appropriate therapeutic targeting approach.MethodsUsing a number of docetaxel-resistant sublines of PC-3 cells, we have undertaken a transcriptomic analysis by expression microarray using the Affymetrix Human Gene 1.0 ST Array and in conjunction with bioinformatic analyses undertook to predict dysregulated TFs in docetaxel resistant prostate cancer. The clinical significance of this prediction was ascertained by performing immunohistochemical (IHC) analysis of an identified TF (SRF) in the metastatic sites from men who died of advanced CRPC. Investigation of the functional role of SRF was examined by manipulating SRF using SiRNA in a docetaxel-resistant PC-3 cell line model.ResultsThe transcription factors identified include serum response factor (SRF), nuclear factor kappa-B (NFκB), heat shock factor protein 1 (HSF1), testicular receptor 2 & 4 (TR2 &4), vitamin-D and retinoid x receptor (VDR-RXR) and oestrogen-receptor 1 (ESR1), which are predicted to be responsible for the differential gene expression observed in docetaxel-resistance. IHC analysis to quantify nuclear expression of the identified TF SRF correlates with both survival from date of bone metastasis (p = 0.003), survival from androgen independence (p = 0.00002), and overall survival from prostate cancer (p = 0.0044). Functional knockdown of SRF by siRNA demonstrated a reversal of apoptotic resistance to docetaxel treatment in the docetaxel-resistant PC-3 cell line model.ConclusionsOur results suggest that SRF could aid in treatment stratification of prostate cancer, and may also represent a therapeutic target in the treatment of men afflicted with advanced prostate cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3100-4) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 89%

The prognostic utility of the transcription factor SRF in docetaxel-resistant prostate cancer: in-vitro discovery and in-vivo validation

et al. 2017

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“…5,6 Further, mitochondrial biogenesis, TCA cycle and OXPHOS signatures correlate with unfavorable outcomes in prostate cancer as well as other cancer types. 3,11,13,15,16,53-56 Inhibition of mitochondrial function/OXPHOS results in cell death or cell cycle arrest in multiple cancer types. 8-10,17 Thus, while glycolysis is a major metabolic pathway in cancer, mitochondrion-mediated functions still appear essential for many cancer cell types including prostate.…”

Section: Discussionmentioning

confidence: 99%

Androgens regulate prostate cancer cell growth via an AMPK-PGC-1α-mediated metabolic switch

et al. 2013

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Prostate cancer is the most commonly diagnosed malignancy among men in industrialized countries, accounting for the second leading cause of cancer-related deaths. While we now know that the androgen receptor (AR) is important for progression to the deadly advanced stages of the disease, it is poorly understood what AR-regulated processes drive this pathology. Here, we demonstrate that AR regulates prostate cancer cell growth via the metabolic sensor 5′-AMP-activated protein kinase (AMPK), a kinase that classically regulates cellular energy homeostasis. In patients, activation of AMPK correlated with prostate cancer progression. Using a combination of radiolabeled assays and emerging metabolomic approaches, we also show that prostate cancer cells respond to androgen treatment by increasing not only rates of glycolysis, as is commonly seen in many cancers, but also glucose and fatty acid oxidation. Importantly, this effect was dependent on androgen-mediated AMPK activity. Our results further indicate that the AMPK-mediated metabolic changes increased intracellular ATP levels and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-mediated mitochondrial biogenesis, affording distinct growth advantages to the prostate cancer cells. Correspondingly, we used outlier analysis to determine that PGC-1α is overexpressed in a subpopulation of clinical cancer samples. This was in contrast to what was observed in immortalized benign human prostate cells and a testosterone-induced rat model of benign prostatic hyperplasia. Taken together, our findings converge to demonstrate that androgens can co-opt the AMPK-PGC-1α signaling cascade, a known homeostatic mechanism, to increase prostate cancer cell growth. The current study points to the potential utility of developing metabolic-targeted therapies directed towards the AMPK-PGC-1α signaling axis for the treatment of prostate cancer.

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“…When normal prostate tissue (NPT) samples are unavailable, benign prostatic hyperplasia (BPH) samples can be used as normal prostate samples for comparison with PCa samples [35,36]. The study group consisted of 25 Han Chinese patients with PCa and 20 Han Chinese individuals with BPH with ages ranging from 60 to 91.…”

Section: Methodsmentioning

confidence: 99%

Identification of candidate miRNA biomarkers from miRNA regulatory network with application to prostate cancer

et al. 2014

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BackgroundMicroRNAs (miRNAs) are a class of non-coding regulatory RNAs approximately 22 nucleotides in length that play a role in a wide range of biological processes. Abnormal miRNA function has been implicated in various human cancers including prostate cancer (PCa). Altered miRNA expression may serve as a biomarker for cancer diagnosis and treatment. However, limited data are available on the role of cancer-specific miRNAs. Integrative computational bioinformatics approaches are effective for the detection of potential outlier miRNAs in cancer.MethodsThe human miRNA-mRNA target network was reconstructed by integrating multiple miRNA-mRNA interaction datasets. Paired miRNA and mRNA expression profiling data in PCa versus benign prostate tissue samples were used as another source of information. These datasets were analyzed with an integrated bioinformatics framework to identify potential PCa miRNA signatures. In vitro q-PCR experiments and further systematic analysis were used to validate these prediction results.ResultsUsing this bioinformatics framework, we identified 39 miRNAs as potential PCa miRNA signatures. Among these miRNAs, 20 had previously been identified as PCa aberrant miRNAs by low-throughput methods, and 16 were shown to be deregulated in other cancers. In vitro q-PCR experiments verified the accuracy of these predictions. miR-648 was identified as a novel candidate PCa miRNA biomarker. Further functional and pathway enrichment analysis confirmed the association of the identified miRNAs with PCa progression.ConclusionsOur analysis revealed the scale-free features of the human miRNA-mRNA interaction network and showed the distinctive topological features of existing cancer miRNA biomarkers from previously published studies. A novel cancer miRNA biomarker prediction framework was designed based on these observations and applied to prostate cancer study. This method could be applied for miRNA biomarker prediction in other cancers.

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Transcriptional profiling of transurethral resection samples provides insight into molecular mechanisms of hormone refractory prostate cancer

Cited by 9 publications

References 16 publications

The prognostic utility of the transcription factor SRF in docetaxel-resistant prostate cancer: in-vitro discovery and in-vivo validation

The prognostic utility of the transcription factor SRF in docetaxel-resistant prostate cancer: in-vitro discovery and in-vivo validation

Androgens regulate prostate cancer cell growth via an AMPK-PGC-1α-mediated metabolic switch

Identification of candidate miRNA biomarkers from miRNA regulatory network with application to prostate cancer

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