Transcriptomic effects of Capridine on the acute promyelocytic leukemia HL-60 cell line
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Dumitru Iacobas
PROVIDER: E-GEOD-72415 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
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
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
Project description:Pulmonary hypertension (PH), a rare disorder is a complication of a number of cardiopulmonary, unrelated systemic diseases, drug toxicity and genetic mutations. Major advances have been made in the field, but the pathogenesis of PH is not yet understood. Several experimental models such as monocrotaline (MCT) and hypoxia have been used to understand the mechanism underlying the pathogenesis of PH. We have recently shown that that the addition of hypoxia to MCT injected rats accelerates the disease process leading to neointima formation. We have profiled the lungs of adult male Sprague-Dawley rats kept for 4 weeks in normal atmospheric conditions or in hypobaric hypoxia (380 mmHg) w/o subcutaneous injection with 40 mg/kg MCT or just saline. While MCT and hypoxia altered expression of few genes when applied separately, together they induced a substantial alteration of the transcriptome. The most profoundly altered pathways by the combined effect of hypoxia and MCT were: endocytosis, apoptosis, HIF-1 signaling pathway and vascular smooth muscle contraction. Two-condition (C = normal atmospheric conditions (control) vs H = hypobaric hypoxia) + two treatment (M = with MCT, O = without MCT) experiment. Four biological replicas of each combination: CO, HO, CM, HM. 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: CO1 & CO3 were compared with CM1 & CM3, CO2 & CO4 were compared with CM2 & + CM4, 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.
2015-09-04 | E-GEOD-72707 | biostudies-arrayexpress
Project description:The transcriptomes of young male and (in estrus) female hypothalami were profiled and compared to learn about the sex dichotomy of the cytoskeletal genomic fabric(CGF), defined as the most inter-coordinately and stably expressed gene web whose encoding proteins form the intracellular scaffolding. RNA samples collected from hypothalami of 4 young rat males and 4 (in estrus) females were hybridized with Agilent rat (4x44k 60 mer features, 4 microarrays per slide) gene expression chips. Novel analytical tools were used to reveal hidden features of the cytoskeletal transcriptome
2012-06-04 | E-GEOD-38450 | biostudies-arrayexpress
Project description:Clear cell renal carcinoma (CCRC) accounts for >80% of all kidney cancers but what triggers the tumorigenesis in the kidney and metastases in the bones are still under debate. Our hypothesis is that remodeling of the genomic fabrics of certain functional pathways and their interplay beyond critical limits are key causes of CCRC. We profiled the transcriptomes of metastatic chest wall and of two primary cancerous sites of the renal medulla and compared them with that of non-cancerous kidney resection margins. Samples were collected from a 74 years old male with metastatic carcinoma, consistent with renal cell carcinoma, clear cell type, Fuhrman grade 3, who undergone total right kidney nephrectomy and resection of a chest wall mass. Transcriptomic analysis pointed the tumor region in the right kidney that led to the chest wall metastases. The tumor proved heterogeneous not only in the expression level but also in the expression control, coordination and interplay of pathways responsible for cellular processes and genetic and environmental information processing. The differently regulated pathways in the two sides of the tumor: CCRC, and HIF-1, Vegfa and mTor signaling indicate activation of distinct mechanisms. Four-conditions (CTR = control - non-cancerous kidney resection margins, PTA = primary tumor side A, PTB = primary tumor side B, MET = chest wall metastasis. Four biological replicates of each condition.
2015-08-24 | E-GEOD-72304 | biostudies-arrayexpress
Project description:Neuropeptide Y (NPY) is an endogenous modulator of neuronal activity by regulating GABA and glutamate release. Previously, we found that estradiol modulates NPY expression in the hippocampal dentate gyrus. Here we investigated which estrogen receptor type activation is required for the NPY expression. Further, we determined effects of estrogen receptor activation on NPY release. Finally, we determined the contribution of estrogen-mediated remodeling of the GABAergic and glutamatergic network in relation to changes in coupling with NPY in ovariectomized rats. We found that activation of either estrogen receptor type increases NPY expression as well as NPY release in the dentate gyrus. We also found that compared to OVX rats, estrogen replacement increases the likeness of synergistic/antagonistic coupling between the NPY and GABAergic synapse genes while the glutamatergic synapse genes are less likely coupled with NPY. The data together suggest that estrogen plays a critical role in regulation of activity of the NPY system and its coupling to GABAergic and glutamatergic synapses in female rat dentate gyrus. Two-conditions (E = beta-estradiol replacement vs O = oil) experiment. Biological replicates: 4E, 4O.
2014-08-02 | E-GEOD-60013 | biostudies-arrayexpress
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.
2013-03-06 | E-GEOD-44858 | biostudies-arrayexpress
Project description:Elevated c-Jun levels result in apoptosis and are evident in neurodegenerative disorders such as Alzheimer's disease and dementia and after global cerebral insults such as stroke and epilepsy. NMDA receptor (NMDAR) antagonists block c-Jun upregulation and prevent neuronal cell death following excitotoxic insults. However, little is known about the molecular mechanisms that regulate c-Jun abundance in neurons. Here we show that PRR7, a component of synaptic junctions, can upregulate c-Jun levels by inhibiting its ubiquitination in neurons. PRR7 interacts with the GLUN1 subunit of NMDARs and is upregulated in the nucleus following NMDAR activation. We show that PRR7 interacts with the E3 ligase SCFFBW7 (FBW7) and blocks the FBW7-mediated ubiquitination of c-Jun. PRR7 overexpression increases c-Jun-dependent transcriptional activity and promotes neuronal death. Microarray assays indicate that both Prr7 knockdown or overexpression alter the abundance of c-Jun-regulated transcripts associated with cellular viability as well as synaptic function. Moreover, Prr7 knockdown attenuates NMDA-mediated excitotoxicity in primary neuronal cultures. Our results show that PRR7 links NMDAR activity to c-Jun function and provide insight into the processes that underlie NMDA-dependent excitotoxicity. Four biological replicas of each of the four conditions: NO = not transduced with virus; NT = transduced with control lentiviruses containing a non-targeting shRNA sequence; KD = transduced with lentiviruses expressing PRR7-specific shRNAs; OE= transduced with lentiviruses to overexpress PRR7.
2014-10-25 | E-GEOD-62686 | biostudies-arrayexpress
Project description:We profiled the whole transcriptomes of female rat hypothalamic arcuate nuclei to determine the remodeling of the genomic fabrics responsible for the glutamatergic, GABAergic, dopaminergic, cholinergic and serotonergic transmission in epilepsy and recovery following different treatments. The rats were prenatally exposed (G15) to betamethasone (or just saline for control) followed by repeated adiministration of N-Methyl-D-Aspartic acid (NMDA) on postnatal days 12, 13 and 15 which triggered infantile spasms. Pups were treated with either ATCH, PMX53 (a potent C5ar1 antagonist) or saline to act as a control, on days 13, 14 and 15 prior to NMDA administration to determine what effects each treatment had on transcriptome recovery. Our Genomic Fabric Paradigm (GFP) is proposed as a transformative research approach to enhance the understanding of the brain transcriptomic alterations in epileptic rats and recovery following various treatments. The genomic fabric of a particular synapse is the structured transcriptome associated with the most interconnected and stably expressed gene network responsible for that type of neurotransmission. GFP refines the description of functional pathways by selecting the most prominent genes and determining their networking. Moreover, it quantifies the remodeling of functional pathways and their interplay in disease and recovery in response to a treatment. We found that priming with betamethasone had substantial consequences on the topology of the genomic fabrics of all kind of synaptic transmission and that NMDA-induced spasms strongly exacerbated the remodeling of these fabrics. Contrary to our findings in male rats, neither ACTH or PMX53 treatment recovered the normal synaptic transcriptomes. One tissue (hypothalamic arcuate nucleus) x two prenatal exposures (B = betamethasone, S = saline) x two conditions for the betamethasone expossed rats (with (Y) without (N) infantile spasms) x three postnatal treatments (A = ACTH, P = PMX53, S = saline) x one sex (M) . Biological replicates: 4 ASNSM, 4 ABNSM, 4 ABYSM, 4 ABYAM, 4 ABYPM. Please note that a the multiple yellow strategy has been adopted, in which differently labeled biological replicas are cohybridized, similarly labeled samples of distinct conditions are compared and the results of the green and red comparisons are averaged.
2016-07-20 | E-GEOD-84585 | biostudies-arrayexpress
Project description:Prenatal exposure to synthetic corticosteroids can significantly alter postnatal development through changes in neurotransmitters 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 prefrontal cortex of female rats prenatally exposed to either betamethasone or saline. The transcriptome has been assessed by novel computational tools to determine complex changes that may have life-long effects on phenotype, i.e., behavior. We analyzed how 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) are afected by the prenatal exposure to corticosteroids and postnatal ketamine-induced seizures. One sex (F) x two prenatal exposures (B = betamethasone, S = saline) x two postnatal treatments (K = ketamine, S = saline). Biological replicates: 4 FSS, 4 FBS, 4 FBK.
2016-01-09 | E-GEOD-76694 | biostudies-arrayexpress