Unknown,Transcriptomics,Genomics,Proteomics

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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 ?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.

ORGANISM(S): Homo sapiens

SUBMITTER: Dumitru Iacobas

PROVIDER: E-GEOD-72333 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Prenatal exposure to synthetic corticosteroids can significantly alter postnatal development through changes in neurotransmitters, peptides and their receptors, and thus having long-lasting behavioral effects. Some of these changes have been observed in animal experiments, others also in humans prenatally exposed to synthetic corticosteroids. Here, we focused on transcriptomic changes within the ARC of rats prenatally exposed to either betamethasone or saline. The expression of transcriptome has been assessed by novel computational tools to determine complex changes that may have life-long effects on phenotype, i.e., behavior. Total of 18,094 unigenes were quantified in the hypothalamic ARC of P14 male and female rats prenatally exposed to betametasone used in this experiment. Out of these genes, Kyoto Encyclopedia for Genes and Genomes (http://www.genome.jp) selected 112 for the dopaminergic synapse, 75 for the GABAergic and 97 for the glutamatergic synapse. We further analyzed composition, topology and modulatory networks of the genomic fabric of the dopaminergic, GABAergic, and glutamatergic synapse (the transcriptome of the most interconnected and stably expressed gene network responsible for specific transmission). Finally we investigated the M-bM-^@M-^\transcriptomic landscapeM-bM-^@M-^] of the GSF in the ARC of P14 males (M) and females (F) prenatally (G15) exposed to betamethasone (B) or saline (S). We combined in one measure (PWR = Pair-Wise Relevance) expression levels, controls and coordination of all pairs that can be formed by synapse genes with the other synapse genes, higher PWRs indicating larger influence of that gene pair to the fabric modulation. We found that prenatal exposure to betamethasone caused sex-dependent changes in the dopaminergic/GABA/glutamatergic synapse genes:. In males, 10 dopaminergic (9%), 4 GABAergic (5%) and 5 glutamatergic synapse genes (5%) were down-regulated. While in females, 9 dopaminergic (8%), 3 GABAergic (4%) and 6 glutamatergic (6%) synapse genes were downregulated. The data indicate that in both sexes the dopaminergic synapse was the most affected. In contrast, in control animals, no significant differences between male and female were present in these synapse genes. Since the most noticeable transcritpomic changes were found in the transcriptome of DA glutamatergic synapse, we investigated the expression of tyrosine-hydroxylase (TH) NMDA receptor subunits in the ARC. The western blot analyses and immunohistochemistry confirmed the sex-specific differences between prenatally betamethasone-exposed and saline-exposed P15 rats. Accordingly to the changes in gene expression, prenatal exposure to synthetic corticosteroids was associated with postnatal changes in behavior and susceptibility to certain types of seizures. While we did not find any significant impairements in normal behavioral patterns (open field activity), there was a sex-specific change in the novel object recognition test. We found that behavioral lateralization in females is lost after prenatal betamethasone exposure and both male and female prenatally betamethasone exposed rats were avoiding novelty. This trait is similar to children with autism and suggests that certain elements of autistic behaviors can be present after prenatal exposure to synthetic corticosteroids. Additionally, there were changes in the search patterns in the Morris water maze as well as in the Barnes maze. In conclusion, our work is consistent with findings of profound reprogramming changes in the brain after prenatal corticosteroid exposure associated with alterations cognitive functions and seizure susceptibility. Two-sexes (M, F) x two-condition (B = betamethasone prenataly exposed vs S = saline prenataly exposed) experiment. Biological replicates: 4 MS, 4 FS, 4 MB, 4 FB.

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

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