scholarly journals Patient-specific Boolean models of signaling networks guide personalized treatments

2021 ◽  
Author(s):  
Arnau Montagud ◽  
Jonas Béal ◽  
Luis Tobalina ◽  
Pauline Traynard ◽  
Vigneshwari Subramanian ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Line ◽  
Growth Conditions ◽  
Molecular Data ◽  
Specific Model ◽  
Patient Specific ◽  
Specific Response ◽  
Precision Oncology ◽  
Boolean Models ◽  
Prostate Cell

Prostate cancer is the second most occurring cancer in men worldwide. To better understand the mechanisms of tumorigenesis and possible treatment responses, we developed a mathematical model of prostate cancer which considers the major signalling pathways known to be deregulated. We personalised this Boolean model to molecular data to reflect the heterogeneity and specific response to perturbations of cancer patients. 488 prostate samples were used to build patient-specific models and compared to available clinical data. Additionally, eight prostate cell-line-specific models were built to validate our approach with dose-response data of several drugs. The effects of single and combined drugs were tested in these models under different growth conditions. We identified 15 actionable points of interventions in one cell-line-specific model whose inactivation hinders tumorigenesis. To validate these results, we tested nine small molecule inhibitors of five of those putative targets and found a dose-dependent effect on four of them, notably those targeting HSP90 and PI3K. These results highlight the predictive power of our personalized Boolean models and illustrate how they can be used for precision oncology.

Cerebellar Degeneration-Related Autoantigen 1 (CDR1) Gene Expression in Prostate Cancer Cell Lines

2014 ◽  
Vol 29 (3) ◽  
pp. 288-290 ◽  
Author(s):  
Michele Salemi ◽  
Filippo Fraggetta ◽  
Antonio Galia ◽  
Pietro Pepe ◽  
Laura Cimino ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Cerebellar Degeneration ◽  
Normal Prostate ◽  
Prostate Cell ◽  
Prostate Cell Line ◽  
Normal Prostate Cell

Prostate cancer (PCa) is the most frequent cancer among men in many developing countries, and the second leading cause of cancer-related death in men. A genetic component has been implicated in PCa onset and development. The cerebellar degeneration-related autoantigen 1 ( CDR1) gene, mapping in Xq26-q27.2, is expressed in cerebrum, cerebellum, heart, lung, liver, and kidney. In addition, CDR1 expression has been detected in neuroblastoma, renal carcinoma cell lines, and other cancer cell lines. In this study, we investigated the expression of the CDR1 gene in the LNCaP and PC-3 PCa cell lines, and in the PNT1A normal prostate cell line. CDR1 mRNA expression was evaluated by qRT-PCR. We found that the CDR1 gene was overexpressed in the LNCaP and PC-3 PCa cell lines as compared with the PNT1A normal prostate cell line. These data suggest that CDR1 could be a new biomarker for PCa identification.

Deleted in cancer 1: Search for a function in prostate cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16095-e16095
Author(s):  
J. Hirsch ◽  
T. Nelius ◽  
C. Pfarr ◽  
W. De Riese ◽  
I. Wieland ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Growth Factor ◽  
Cell Line ◽  
Cell Lines ◽  
Expression Profiling ◽  
Ectopic Expression ◽  
Mrna Levels ◽  
Normal Prostate ◽  
Prostate Cell ◽  
Growth Inhibitory

e16095 Background: Deleted In Cancer 1 (DICE1/INTS6) gene was recently identified to colocalize with the microsatellite marker D13S284 in 13q14.3, a region frequently affected by allelic deletion in many solid tumors including prostate cancer (PrCa). DICE1 missense mutations have been previously detected in PrCa cell line LNCap, and reduced DICE1 expression appears to be associated with CpG promoter hypermethylation in PrCa cells. DICE1 is a highly conserved nuclear protein suggesting its involvement in DNA repair, transcription, or RNA splicing. In mouse, the DICE1 homologue interferes with the response to insulin-like growth factor 1 and suppresses anchorage-independent growth of transformed mouse cells. The totality of these results suggests that DICE1 is a tumor suppressor gene and insist on the need to better characterize DICE1 function in PrCa. Methods: Expression of DICE1 was evaluated by Northern Blot in PrCa cell lines LNCap, DU145, PC3, PC3ml and CPTX1532 and compared to expression level in normal prostate cell line NPTX1532. DICE1 growth inhibitory effects were analyzed by colony formation assay on PC3 and DU145 cells transfected with DICE1 expression plasmid or control vector. Apoptosis was assessed by visualization of genomic DNA fragmentation on agarose gel. PCR arrays (SABiosciences) were used to identify specific signaling pathways modulated in response to DICE1 expression. Results: Markedly decreased DICE1 mRNA levels were detected in PrCa cell lines LNCap, DU145, PC3 and PC3ml as well as CPTX1532 as compared to NPTX1532, a cell line derived from normal prostate tissue. Ectopic expression of DICE1 cDNA in DU145 and PC3 cells substantially suppressed their ability to form colonies in vitro. This growth inhibition was not due to immediate induction of apoptosis suggesting growth suppression by other pathways. Expression profiling identified multiple pathways, such as Wnt, Hedgehog, PI-3 Kinase, NFκB and Insulin pathways, regulated in response to ectopic DICE1 expression. Furthermore, various transcription factors including Fos, Jun, CEBPA and PPAR-γ were up-regulated in response to DICE1. Conclusions: These results clearly illustrate the growth inhibitory ability of DICE1 in PrCa. Expression profiling links DICE1 function to growth factor signaling and cell-cell communication. No significant financial relationships to disclose.

scholarly journals Integrative proteomic and phosphoproteomic profiling of prostate cell lines

2019 ◽  
Author(s):  
Maria Katsogiannou ◽  
Jean-Baptiste Boyer ◽  
Alberto Valdeolivas ◽  
Elisabeth Remy ◽  
Laurence Calzone ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Differentially Expressed ◽  
Migration And Invasion ◽  
Mass Spectrometry Experiment ◽  
Disease Etiology ◽  
Prostate Cell ◽  
Functional Features ◽  
Prostate Cell Lines

ABSTRACTBackgroundProstate cancer is a major public health issue, mainly because patients relapse after androgen deprivation therapy. Proteomic strategies, aiming to reflect the functional activity of cells, are nowadays among the leading approaches to tackle the challenges not only of better diagnosis, but also of unraveling mechanistic details related to disease etiology and progression.MethodsWe conducted here a large SILAC-based Mass Spectrometry experiment to map the proteomes and phosphoproteomes of four widely used prostate cell lines, namely PNT1A, LNCaP, DU145 and PC3, representative of different cancerous and hormonal status.ResultsWe identified more than 3000 proteins and phosphosites, from which we quantified more than 1000 proteins and 500 phosphosites after stringent filtering. Extensive exploration of this proteomics and phosphoproteomics dataset allowed characterizing housekeeping as well as cell-line specific proteins, phosphosites and functional features of each cell line. In addition, by comparing the sensitive and resistant cell lines, we identified protein and phosphosites differentially expressed in the resistance context. Further data integration in a molecular network highlighted the differentially expressed pathways, in particular migration and invasion, RNA splicing, DNA damage repair response and transcription regulation.ConclusionsOverall, this study proposes a valuable resource toward the characterization of proteome and phosphoproteome of four widely used prostate cell lines and reveals candidates to be involved in prostate cancer progression for further experimental validation.

scholarly journals NVP-BEZ235 Enhances Radiosensitivity of Human Prostate Cancer Cells but Acts as a Radioprotector to Normal Prostate Cells

2015 ◽  
Vol 1 (1) ◽  
Author(s):  
Sechaba Maleka ◽  
Antonio Serafin ◽  
Roswita Hamunyela ◽  
Mogammad Hamid ◽  
Daniel Achel ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Line ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
Specific Inhibitor ◽  
Cellular Heterogeneity ◽  
Radiation Response ◽  
Human Prostate ◽  
Normal Prostate ◽  
Prostate Cell

Targeted therapy for prostate cancer may offer potential improvement over current conventional therapies because of its specificity. Although conventional treatments are effective, they are not always curative, andhave several limitations. In prostate cancer, activation of the epidermal growth factor receptor (EGFR) and the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways have been implicatedin tumorigenesis, and resistance to both conventional and targeted anticancer therapies. Single-target therapies may fail due to cellular heterogeneity. Concomitant targeting of EGFR and PI3K/mTOR cell signaling components may enhance the efficacy of radiotherapy. In this study, the effect of an EGFR inhibitor (AG-1478) and a dual inhibitor of PI3K and mTOR (NVP-BEZ235) on the radiation response of a human prostate carcinoma cell line (DU145) and a normal prostate cell line (1542N) was investigated, using the colony forming assay. Treatment ofDU145 cells with AG-1478 and NVP-BEZ235, either singly or in combination, resulted in a slight radiosensitisation of DU145 cells. Neither AG-1478 nor a cocktail of both inhibitors had an effect on the radiation response of the 1542N cell line. Interestingly, NVP-BEZ235 significantly protected 1542N cells from radiation-induced cell death. These data suggest that a specific inhibitor of PI3K and mTOR (NVP-BEZ235) could potentially be effective as a radio-protector.

In vitro dorsal root ganglia and human prostate cell line interaction: Redefining perineural invasion in prostate cancer

The Prostate ◽  
2001 ◽  
Vol 49 (3) ◽  
pp. 213-223 ◽  
Author(s):  
Gustavo E. Ayala ◽  
Thomas M. Wheeler ◽  
H. David Shine ◽  
Monika Schmelz ◽  
Ana Frolov ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Line ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Perineural Invasion ◽  
Human Prostate ◽  
Prostate Cell ◽  
Prostate Cell Line

scholarly journals Chlamydia trachomatis Growth and Cytokine mRNA Response in a Prostate Cancer Cell Line

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Ivan M. Petyaev ◽  
Naylia A. Zigangirova ◽  
Elena Y. Morgunova ◽  
Nigel H. Kyle ◽  
Elena D. Fedina ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Line ◽  
Cancer Cell ◽  
Early Phase ◽  
Prostate Cancer Cell ◽  
Cancer Cell Line ◽  
Prostate Cancer Cell Line ◽  
Immunofluorescent Staining ◽  
Prostate Cell ◽  
Infectious Cycle

In the present paper, we report that C. trachomatis can be efficiently propagated and affect mRNA expression for two major cytokines, relevant to tumor progression, in CWR-R1 cells, a malignant prostate cell line. CWR-R1 and McCoy cells, a classic cell line for chlamydial research, were grown and infected with C. trachomatis under similar conditions. Cell monolayers were harvested for RNA analysis and immunostaining with major outer membrane protein (MOMP) antibody at 24, 48, and 72 hours of the postinfection (hpi) period. It was shown that the infectious cycle of chlamydial pathogen in CWR-R1 cells resembles the progression of C. trachomatis infection in McCoy cells but with a few important differences. First of all, the initial stage of C. trachomatis propagation in CWR-R1 cells (24 hpi) was characterized by larger inclusion bodies and more intense, specific immunofluorescent staining of infected cells as compared with McCoy cells. Moreover, there was a corresponding increase in infective progeny formation in CWR-R1 cells along with mRNA for EUO, a crucial gene controlling the early phase of the chlamydial development cycle (24 hpi). These changes were more minimal and became statistically insignificant at a later time point in the infectious cycle (48 hpi). Altogether, these data suggest that the early phase of C. trachomatis infection in CWR-R1 cells is accompanied by more efficient propagation of the pathogen as compared with the growth of C. trachomatis in McCoy cells. Furthermore, propagation of C. trachomatis in CWR-R1 cells leads to enhanced transcription of interleukin-6 and fibroblast growth factor-2, genes encoding two important proinflammatory cytokines implicated in the molecular mechanisms of chemoresistance of prostate cancer and its ability to metastasize. The possible roles of reactive oxygen species and impaired mitochondrial oxidation in the prostate cancer cell line are discussed as factors promoting the early stages of C. trachomatis growth in CWR-R1 cells.

scholarly journals Cancer-driven IgG promotes the development of castration-resistant Prostate Cancer though the SOX2-CIgG pathway

2020 ◽  
Author(s):  
Caipeng Qin ◽  
Zhengzuo Sheng ◽  
Xinmei Huang ◽  
Jingshu Tang ◽  
Yang Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Line ◽  
Androgen Deprivation Therapy ◽  
Xenograft Model ◽  
Androgen Deprivation ◽  
Cancer Tissue ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cell ◽  
Castration Resistant ◽  
Mouse Xenograft Model

Abstract Background: Although Androgen deprivation therapy (ADT) is the initial treatment strategy for prostate cancer, recurrent castration-resistant prostate cancer (CRPC) eventually ensues. In this study, cancer-derived immunoglobulin G(CIgG) was found to be induced after ADT, identifying CIgG as a potential CRPC driver gene.Methods: The expression of CIgG and its clinical significance in prostate cancer tissue was analyzed by TCGA database and immunohistochemistry. Subsequently, the sequence features of prostate cell line (LNcap, DU145, PC3) VHDJH rearrangements were analyzed via comparison with the best matching functional germline IgVH, IgDH and IgJH genes. We also assessed the effect of CIgG on the migratory, invasive and proliferative abilities of prostate cancer cells in vitro and vivo. Cells with high CIgG expression (CIgGhigh) and low CIgG expression (CIgG-/low) from the PC3 cell line were sorted by FACS using a CIgG monoclonal antibody named RP215, then, suspended microsphere, colony formation and drug-resistant assays were performed. A NOD/SCID mouse tumor xenograft model was developed for the study of the tumorigenic effects of the different cell populations. The AR-SOX2-CIgG signaling pathway was validated by immunohistochemistry, immunofluorescence, qRT-PCR, Western blot, luciferase and ChIP assays and bioinformatics analyses. Finally, we investigated the effect of RP215 inhibition on the progression of prostate cancer in vivo using a Babl/c nude mouse xenograft model.Results: We demonstrated that CIgG was induced by androgen deprivation therapy (ADT) and upregulated by SOX2 [SRY (sex determining region Y)-box 2] in prostate cancer, which may promote the development of CRPC. In addition, our findings underscore a novel role of CIgG signaling in the maintenance of stemness and the progression of cancer through MARK/ERK and AKT in prostate cancer.Conclusion: Our data suggests that CIgG could be a driver of CRPC development, and that targeting the SOX2-CIgG axis may therefore inhibit CRPC development after ADT.

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