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Remodeling of major genomic fabrics and their interplay in Capridine-treated DU145 classic human prostate cancer

ABSTRACT: Our preclinical developmental program identified Capridine as a chemotherapeutic agent that had specificity towards prostate cancer with minimal bone marrow toxicity. In human prostate cancer xenograft studies both androgen responsive and non-responsive tumors were inhibited by a weekly therapeutic regimen Capridine. The minimal bone marrow toxicity as seen in rodent and dog preclinical studies is in line with its twenty-fold differential activity in prostate cancer cells vs. the promyelocytic leukemic cell line HL-60. This differential activity was partly attributed to its activity on γH2AX modulation, which was considered as one of the targets. Capridine structure is consistent with a classical DNA intercalating agent; however, its DNA intercalation property does not fully correlate with its anti prostate cancer specific activity. To identify the cellular targets of Capridine in a more comprehensive manner we analyzed its transcriptomic effects on androgen non-responsive DU145 cells. Agilent human gene expression microarray analysis indicated that expression of 97 unigenes genes was altered by Capridine. Our data confirm that, in addition to DNA intercalation, Capridine targets DNA transcription via histone modulation in a cell-specific manner.

ORGANISM(S): Homo sapiens

PROVIDER: GSE72333 | GEO | 2015/08/25

SECONDARY ACCESSION(S): PRJNA293762

REPOSITORIES: GEO

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Remodeling of major genomic fabrics and their interplay in Capridine-treated DU145 classic human prostate cancer

Project description:Our preclinical developmental program identified Capridine as a chemotherapeutic agent that had specificity towards prostate cancer with minimal bone marrow toxicity. In human prostate cancer xenograft studies both androgen responsive and non-responsive tumors were inhibited by a weekly therapeutic regimen Capridine. The minimal bone marrow toxicity as seen in rodent and dog preclinical studies is in line with its twenty-fold differential activity in prostate cancer cells vs. the promyelocytic leukemic cell line HL-60. This differential activity was partly attributed to its activity on ?H2AX modulation, which was considered as one of the targets. Capridine structure is consistent with a classical DNA intercalating agent; however, its DNA intercalation property does not fully correlate with its anti prostate cancer specific activity. To identify the cellular targets of Capridine in a more comprehensive manner we analyzed its transcriptomic effects on androgen non-responsive DU145 cells. Agilent human gene expression microarray analysis indicated that expression of 97 unigenes genes was altered by Capridine. Our data confirm that, in addition to DNA intercalation, Capridine targets DNA transcription via histone modulation in a cell-specific manner. Two-conditions: DO = not treated, DA = Capridine-treated DU145 cells. Four biological replicates of each condition. Differently labeled biological replicates were cohybridized with each array. Results of similarly labeled different conditions were compared then averaged for the two fluorescent labels. For instance: DO1 & DO3 were compared with DA1 & DA3, DO2 & DO4 were compared with DA2 & + DA4, and the results of the comparisons averaged. This design uses 100% of the resources, has a better normlaiztion and allows all possible comparisons among the conditions.

2015-08-25 | E-GEOD-72333 | biostudies-arrayexpress

Remodeling of DNA transcription genomic fabric in Capridine-treated LNCaP human prostate cancer cell line

2015-08-27 | GSE72414 | GEO

Remodeling of DNA transcription genomic fabric in Capridine-treated LNCaP human prostate cancer cell line

Project description:Capridine is a chemotherapeutic agent with specificity towards prostate cancer and minimal bone marrow toxicity. Capridine structure is consistent with a classical DNA intercalating agent, although its DNA intercalation property does not fully correlate with its anti prostate cancer specific activity. We have used Agilent human gene expression arrays to identify the cellular targets of Capridine on androgen responsive LNCaP cells, a classical cell lines for prostate cancer studies. We found that expression of 142 unigenes genes was altered by Capridine. Interestingly, the most altered category was that of transcription regulators: 10 down and 16 upregulated. Our data confirm that, in addition to DNA intercalation, Capridine targets DNA transcription via histone modulation in a cell-specific manner. Two-conditions: LO = not treated, LA = Capridine-treated DU145 cells. Four biological replicates of each condition. Differently labeled biological replicates were cohybridized with each array. Results of similarly labeled different conditions were compared then averaged for the two fluorescent labels. For instance: LO1 & LO3 were compared with LA1 & LA3, LO2 & LO4 were compared with LA2 & + LA4, and the results of the comparisons averaged. This design uses 100% of the resources, has a better normlaiztion and allows all possible comparisons among the conditions.

2015-08-27 | E-GEOD-72414 | biostudies-arrayexpress

Montagud2022 - Prostate cancer Boolean model

Project description:Prostate cancer is the second most occurring cancer in men worldwide, and with the advances made with screening for prostate-specific antigen, it has been prone to early diagnosis and over-treatment. 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. The model includes pathways such as androgen receptor, MAPK, Wnt, NFkB, PI3K/AKT, MAPK, mTOR, SHH, the cell cycle, the epithelial-mesenchymal transition (EMT), apoptosis and DNA damage pathways. The final model accounts for 133 nodes and 449 edges. We applied a methodology to personalise this Boolean model to molecular data to reflect the heterogeneity and specific response to perturbations of cancer patients, using TCGA and GDSC datasets.

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Prostate Cancer Risk SNPs in Androgen Receptor Target Sites

Project description:We profiled androgen receptor (AR) genomic targets using high-throughput sequencing of chromatin-immunoprecipitated (ChIP) DNA from TMPRSS2-ERG fusion gene positive DUCaP prostate cancer cells. ChIp-seq and microarray gene expression profiling datasets were integrated with the NHGRI GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor binding sites (ARBSs). Eighty GWAS index or linked SNPs were found to be localized in ARBSs. Among these rs11891426:T>G in the 7th intron of the melanophilin gene was found located within a novel putative auxiliary AR binding motif, which we found enriched in the neighborhood of canonical androgen responsive elements. T→G exchange attenuated the transcriptional activity of the ARBS in an AR reporter gene assay of prostate cancer cell models. It went also in line with decreased melanophilin protein level in primary prostate tumors with G allele.These results unravel a hidden link between androgen receptor and a functional PCa risk SNP, whose allele alteration affects androgen regulation of its host gene melanophilin . Genomic profile of androgen receptor binding sites of androgen or vehicle treated DUCaP cells using ChIP-seq. IgG precipiated DNAs from both treatments served as controls.

2015-07-10 | E-GEOD-70679 | biostudies-arrayexpress

Regulation of androgen receptor transcriptional activity and specificity by RNF6

Project description:The androgen receptor (AR) plays a critical role in prostate cancer. We identified an ubiquitin E3 ligase RNF6 as one of AR-associated proteins in a proteomic screening. RNF6 induces AR ubiquitination and promotes AR transcriptional activity. Specific knockdown of the endogenous RNF6 alters expression of a subset of AR target genes and diminishes recruitment of AR and its coactivators to androgen responsive elements (AREs) present in the regulatory region of these genes. Furthermore, RNF6 is overexpressed in human hormone-refractory prostate cancer tissues and required for prostate cancer cell growth under androgen-depleted conditions. Our work has provided a novel mechanism by which AR transcriptional activity and specificity is regulated, and identified RNF6 as a potential new target for prostate cancer treatment.

2009-04-06 | GSE14575 | GEO

Genome-wide characterization of gene expression variations and DNA copy number changes in prostate cancer cell lines

Project description:This SuperSeries is composed of the following subset Series: GSE4016: Gene expression variations in prostate cancer cell lines GSE4017: DNA copy number changes in prostate cancer cell lines Abstract: BACKGROUND: The aim of this study was to characterize gene expression and DNA copy number profiles in androgen sensitive (AS) and androgen insensitive (AI) prostate cancer cell lines on a genome-wide scale. METHODS: Gene expression profiles and DNA copy number changes were examined using DNA microarrays in eight commonly used prostate cancer cell lines. Chromosomal regions with DNA copy number changes were identified using cluster along chromosome (CLAC). RESULTS: There were discrete differences in gene expression patterns between AS and AI cells that were not limited to androgen-responsive genes. AI cells displayed more DNA copy number changes, especially amplifications, than AS cells. The gene expression profiles of cell lines showed limited similarities to prostate tumors harvested at surgery. CONCLUSIONS: AS and AI cell lines are different in their transcriptional programs and degree of DNA copy number alterations. This dataset provides a context for the use of prostate cancer cell lines as models for clinical cancers. Refer to individual Series

2006-03-07 | E-GEOD-4396 | biostudies-arrayexpress

Transcriptional programs activated by exposure of human prostate cancer cells to androgen.

Project description:Androgens are required for both normal prostate development and prostate carcinogenesis. We used DNA microarrays, representing approximately 18,000 genes, to examine the temporal program of gene expression following treatment of the human prostate cancer cell line LNCaP with a synthetic androgen. We observed statistically significant changes in levels of transcripts of more than 500 genes. Many of these genes were previously reported androgen targets, but most were not previously known to be regulated by androgens. The androgen-induced expression programs in 3 additional androgen-responsive human prostate cancer cell lines, and in 4 androgen-independent subclones derived from LNCaP, shared many features with those observed in LNCaP, but some differences were observed. A remarkable fraction of the genes induced by androgen appeared to be related to production of seminal fluid and these genes included many that play roles in protein folding, trafficking, and secretion. Prostate cancer cell lines retain features of androgen responsiveness that reflect normal prostatic physiology. These results provide a broad view of the effect of androgen signaling on the transcriptional program in these cancer cells, and a foundation for further studies of androgen action Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Computed

2005-10-15 | E-GEOD-3451 | biostudies-arrayexpress

Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth

Project description:Alteration of the PTEN/PI3K pathway is associated with late stage and castrate resistant prostate cancer (CRPC). However, how PTEN loss involves in CRPC development is not clear. Here we show that castration-resistant growth is an intrinsic property of Pten-null prostate cancer (CaP) cells, independent of cancer development stage.PTEN loss suppresses androgen-responsive gene expressions by modulating androgen receptor (AR) transcription factor activity. Conditional deletion of AR in the epithelium promotes the proliferation of Pten-null cancer cells, at least in part, by down-regulating androgen-responsive gene FKBP5 and preventing PHLPP-mediated AKT inhibition. Our findings identify PI3K and AR pathway crosstalk as a mechanism of CRPC development, with potentially important implications for CaP etiology and therapy

2011-05-03 | GSE29010 | GEO

DNA copy number changes in prostate cancer cell lines

Project description:Abstract: BACKGROUND: The aim of this study was to characterize gene expression and DNA copy number profiles in androgen sensitive (AS) and androgen insensitive (AI) prostate cancer cell lines on a genome-wide scale. METHODS: Gene expression profiles and DNA copy number changes were examined using DNA microarrays in eight commonly used prostate cancer cell lines. Chromosomal regions with DNA copy number changes were identified using cluster along chromosome (CLAC). RESULTS: There were discrete differences in gene expression patterns between AS and AI cells that were not limited to androgen-responsive genes. AI cells displayed more DNA copy number changes, especially amplifications, than AS cells. The gene expression profiles of cell lines showed limited similarities to prostate tumors harvested at surgery. CONCLUSIONS: AS and AI cell lines are different in their transcriptional programs and degree of DNA copy number alterations. This dataset provides a context for the use of prostate cancer cell lines as models for clinical cancers. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Computed

2006-01-11 | E-GEOD-4017 | biostudies-arrayexpress

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