Longitudinal analysis of androgen deprivation of prostate cancer cells identifies pathways to androgen independence

D’Antonio, Jason M.; Ma, Changqing; Monzon, Federico A.; Pflug, Beth R.

doi:10.1002/pros.20677

Cited by 44 publications

(51 citation statements)

References 51 publications

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“…8,9,12,43 Our study confirms the activation of mTORC1 in CR-LNCaP tumors. However, the effects on AKT appear more complex considering our findings of increased AKT1-Thr308P and reduced AKT1-Ser473P in comparison with hormone-sensitive tumors.…”

Section: Discussionsupporting

confidence: 91%

“…45 The regulation of PAK2 and YAP1 by androgens could be mediated to some extent by transcriptional repression, as it is has been reported that long-term hormone depletion may lead to increased mRNA levels PAK2 and YAP1. 43 However, our own transcriptomic analysis in vivo failed to confirm those findings. Alternatively, posttranslational mechanisms may have a role, especially in the case of YAP1 whose activity is known to be regulated through controlled, ubiquitin-mediated proteolysis.…”

Section: Discussionmentioning

confidence: 84%

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In vivo quantitative phosphoproteomic profiling identifies novel regulators of castration-resistant prostate cancer growth

et al. 2014

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Prostate cancer remains a leading cause of cancer-related mortality worldwide owing to our inability to treat effectively castration-resistant tumors. To understand the signaling mechanisms sustaining castration-resistant growth, we implemented a mass spectrometry-based quantitative proteomic approach and use it to compare protein phosphorylation in orthotopic xenograft tumors grown in either intact or castrated mice. This investigation identified changes in phosphorylation of signaling proteins such as MEK, LYN, PRAS40, YAP1 and PAK2, indicating the concomitant activation of several oncogenic pathways in castration-resistant tumors, a notion that was confirmed by tumor transcriptome analysis. Further analysis demonstrated that the activation of mTORC1, PAK2 and the increased levels of YAP1 in castration-resistant tumors can be explained by the loss of androgen inhibitory actions. The analysis of clinical samples demonstrated elevated levels of PAK2 and YAP1 in castration-resistant tumors, whereas knockdown experiments in androgen-independent cells demonstrated that both YAP1 and PAK2 regulate cell colony formation and cell invasion activity. PAK2 also influenced cell proliferation and mitotic timing. Interestingly, these phenotypic changes occur in the absence of obvious alterations in the activity of AKT, MAPK or mTORC1 pathways, suggesting that PAK2 and YAP1 may represent novel targets for the treatment of castration-resistant prostate cancer. Pharmacologic inhibitors of PAK2 (PF-3758309) and YAP1 (Verteporfin) were able to inhibit the growth of androgen-independent PC3 xenografts. This work demonstrates the power of applying high-resolution mass spectrometry in the proteomic profiling of tumors grown in vivo for the identification of novel and clinically relevant regulatory proteins.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 84%

In vivo quantitative phosphoproteomic profiling identifies novel regulators of castration-resistant prostate cancer growth

et al. 2014

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“…This unexpected phenomenon prompted us to consider other gene loci that may be involved in metastasis prediction. It seemed reasonable that these genes may refl ect endocrine therapy which is known to fail in many metastatic cases [ 19,20 ] . We selected three gene loci from our expression/sensitivity gene pattern ( Table 4 ).…”

Section: O L E C U L a R P H E N O T Y P I N G O F T U M O U R C E mentioning

confidence: 99%

Molecular phenotyping of circulating tumour cells in patients with prostate cancer: prediction of distant metastases

Giesing¹,

Driesel²,

Molitor³

et al. 2012

BJU International

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What's known on the subject? and What does the study add?The role of circulating cancer cells in metastogenesis is generally accepted. Two forms of these cells have been reported in a number of studies, cancer cell clusters (CCCs) and individual epithelial cancer cells. Clusters appear at higher frequencies in the blood. CCCs have been reported to be rich in vimentin and poor in E‐cadherin expression The resulting epithelial to mesenchymal transition, a prerequisite for metastasis formation, occurs in CCCs. We have developed a new set of biomarkers, namely the antioxidant genes GPX1, SOD2 and TXNRD1, specific to cell trafficking in the blood.Firstly, the study shows that diagnosis of distant metastases is feasible by applying molecular phenotyping with a five gene test that has 94% sensitivity and 81% accuracy. Again SOD2 and GPX1 showed the highest sensitivities. Secondly, the study shows the efficacy of palliative chemotherapy in clearing the blood of CCCs overexpressing diagnostic genes. Clinically the overall lifespan ranged from 5 to 99 months under taxotere. We aimed to investigate the molecular reasons and found that MDR1 overexpression worsened survival by 31%. To the best of our knowledge, this is the first study to show the clinical impact of drug targeting and the counter‐effect of drug resistance in CCCs on overall survival. The findings may, therefore, add a novel tool for clinicians in tailoring therapies individually.OBJECTIVES To find the molecular phenotype in circulating cancer cells from patients with prostate cancer (PCa) in order to predict distant metastases. To determine genes affecting the study endpoints of overall survival and time to progression. PATIENTS AND METHODS Twenty‐five urologists in several clinics participated in the study, with 51 patients with metastatic and 77 with non‐metastatic PCa. Molecular analysis was carried out in two forms of circulating cancer cells, cancer cell clusters (CCCs) and individual epithelial cancer cells (CECs). Gene expression was studied using real‐time reverse‐transcriptase PCR. Cycle threshold values were normalized with glyceraldehyde 3‐phosphate dehydrogenase in cancer cells and mononucleated cells, yielding comparative specific expression values from the relative quantification method with the help of the standard curve method for each patient and each gene locus. RESULTS Preclinical validation was performed using aggregated and non‐aggregated SW480 cells showing the independence of CCCs and CECs. Prediction of metastases was achieved with five genes showing the highest sensitivity, SOD2, GPX1, AR, cyclin B and bFGF. The following results were obtained: 94% sensitivity, 65% specificity, 76% positive predictive value and 89% negative predictive value. The prevalence was 63%. Test accuracy was 81% with an odds ratio of 32 (P < 0.001). Overall survival was worsened by preceding chemotherapies when leaving insufficient GPX1 clearance in blood. Drug resistance genes were found to worsen the endpoints, among them MDR1 (P = 0.003; hazard ratio: 1.31; 95% CI: 1.09–1.58). CONCLUSIONS SOD2, GPX1 and AR represent a novel biomarker set for circulating cancer cells (clusters and scattered individual cells) in PCa. The clinical usefulness of these biomarkers ranges from the prediction of clinical tumours to disease prognostication, therapy monitoring and therapy outcome prediction (hormonal therapies, chemotherapies). The presence of CCCs and CECs after batch isolation allows the addition of genes for intensive studies, e.g. drug resistance.

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“…This generated 608 publications. After reviewing abstracts of these publications and selecting only those signatures that had been tested in men with prostate cancer undergoing prostatectomy we identified 34 expression signatures associated with prostate cancer outcomes[3,[26][27][28][29][30][31][32][33][34]. For each signature, genes were mapped to an array feature to measure the expression.…”

mentioning

confidence: 99%

Tissue-based Genomics Augments Post-prostatectomy Risk Stratification in a Natural History Cohort of Intermediate- and High-Risk Men

et al. 2016

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Longitudinal analysis of androgen deprivation of prostate cancer cells identifies pathways to androgen independence

Cited by 44 publications

References 51 publications

In vivo quantitative phosphoproteomic profiling identifies novel regulators of castration-resistant prostate cancer growth

In vivo quantitative phosphoproteomic profiling identifies novel regulators of castration-resistant prostate cancer growth

Molecular phenotyping of circulating tumour cells in patients with prostate cancer: prediction of distant metastases

Tissue-based Genomics Augments Post-prostatectomy Risk Stratification in a Natural History Cohort of Intermediate- and High-Risk Men

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