Transplanted human organoids empower PK/PD assessment of drug candidate for the clinic
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PROVIDER: PRJNA693268 | ENA |
REPOSITORIES: ENA
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Project description:Pharmacokinetic/pharmacodynamic (PK/PD) studies are an essential component of pre-clinical drug discovery. Current best approaches for PK/PD studies, including the analysis of novel kidney disease targeting therapeutic agents, are limited to animal models with unclear translatability to the human condition. To address this challenge, we developed a novel approach for PK/PD studies using transplanted human kidney organoids. We performed PK studies with GFB-887, an investigational new drug now in Phase 2 trials. Orally dosed GFB-887 to athymic rats that had undergone organoid transplantation resulted in measurable drug exposure in human transplanted organoids. Importantly, we established the efficacy of orally dosed GFB-887 in PD studies, where quantitative analysis showed significant protection of kidney filter cells in human organoids and endogenous rat host kidneys. This widely applicable approach demonstrates, for the first time, feasibility of using transplanted human organoids in PK/PD studies, empowering organoids to revolutionize drug discovery.
2022-06-14 | GSE165104 | GEO
Project description:Macrococcus sp. PK strain:PK Genome sequencing and assembly
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Project description:Thermococcus sp. PK genome sequencing project
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Project description:Epigenetic gene silencing by aberrant DNA methylation is one of the important mechanisms leading to the loss of key cellular pathways in tumorigenesis. We have previously reported that IRX4 (Iroquois homeobox 4) was highly downregulated by promoter hypermethylation in pancreatic cancer cell lines as well as in resected primary pancreatic cancers. Based on these data, we have constructed a tetracycline-inducible IRX4 expressing system using pancreatic cancer cell lines PK-1 and PK-9. IRX4 induction significantly suppressed cell growth and caused apoptosis in both PK-1 and PK-9. Because IRX4 is a sequence-specific transcription factor, we tried to analyze IRX4 downstream events by performing microarray analyses using IRX4 inducible PK-1 cells with or without tetracycline. We found that IRX4 induction upregulated several genes that had tumor suppressive functions such as PRDM1, CRYAB, and IL32, and downregulated several genes that had oncogenic functions such as PTCH1, CD36, TFAP2C, and MUC4. These results suggest that DNA methylation-mediated silencing of IRX4 may contribute to pancreatic tumorigenesis through aberrant transcriptional regulation of cancer-related genes.
2020-10-11 | GSE141246 | GEO
Project description:DNA-dependent protein kinase catalitic subunit (DNA-PK) is associated with aggressive disease. DNA-PK plays a role in transcriptional regulation of cancer-relevent pathways but it is not well understood. This study uses transcriptomic analyses to understand the transcriptional role of DNA-PK in castration resistent prostate cancer (CRPC) upon DNA-PK inhibition
2019-08-11 | GSE116765 | GEO
Project description:We used RNA-seq to investigate the functional role of CSFV NS4A in PK-15 cells.we used RNA-seq to investigate the functional role of CSFV NS4A in PK-15 cells.
2022-09-07 | GSE212691 | GEO
Project description:Objective Cancer cells convert more glucose into lactate than healthy cells, what results in their growth advantage. Pyruvate kinase (PK) is a key rate limiting enzyme in this process, what makes it a promising potential therapeutic target. However, currently it is still unclear what consequences the inhibition of PK has on cellular processes. Here, we systematically investigate the consequences of PK depletion for gene expression, histone modifications and metabolism. Methods Epigenetic, transcriptional and metabolic targets were analysed in different cellular and animal models with stable knockdown or knockout of PK. Results Depleting PK activity reduces the glycolytic flux and causes accumulation of glucose-6-phosphate (G6P). Such metabolic perturbation results in stimulation of the activity of a heterodimeric pair of transcription factors MondoA and MLX but not in a major reprogramming of the global H3K9ac and H3K4me3 histone modification landscape. The MondoA:MLX heterodimer upregulates expression of thioredoxin-interacting protein (TXNIP) – a tumour suppressor with multifaceted anticancer activity. This effect of TXNIP upregulation extends beyond immortalised cancer cell lines and is applicable to multiple cellular and animal models. Conclusions Our work shows that actions of often pro-tumorigenic PK and anti-tumorigenic TXNIP are tightly linked via a glycolytic intermediate. We suggest that PK depletion stimulates the activity of MondoA:MLX transcription factor heterodimers and subsequently, increases cellular TXNIP levels. TXNIP-mediated inhibition of thioredoxin (TXN) can reduce the ability of cells to scavenge reactive oxygen species (ROS) leading to the oxidative damage of cellular structures including DNA. These findings highlight an important regulatory axis affecting tumour suppression mechanisms and provide an attractive opportunity for combination cancer therapies targeting glycolytic activity and ROS-generating pathways
2023-07-06 | GSE235388 | GEO
Project description:Objective Cancer cells convert more glucose into lactate than healthy cells, what results in their growth advantage. Pyruvate kinase (PK) is a key rate limiting enzyme in this process, what makes it a promising potential therapeutic target. However, currently it is still unclear what consequences the inhibition of PK has on cellular processes. Here, we systematically investigate the consequences of PK depletion for gene expression, histone modifications and metabolism. Methods Epigenetic, transcriptional and metabolic targets were analysed in different cellular and animal models with stable knockdown or knockout of PK. Results Depleting PK activity reduces the glycolytic flux and causes accumulation of glucose-6-phosphate (G6P). Such metabolic perturbation results in stimulation of the activity of a heterodimeric pair of transcription factors MondoA and MLX but not in a major reprogramming of the global H3K9ac and H3K4me3 histone modification landscape. The MondoA:MLX heterodimer upregulates expression of thioredoxin-interacting protein (TXNIP) – a tumour suppressor with multifaceted anticancer activity. This effect of TXNIP upregulation extends beyond immortalised cancer cell lines and is applicable to multiple cellular and animal models. Conclusions Our work shows that actions of often pro-tumorigenic PK and anti-tumorigenic TXNIP are tightly linked via a glycolytic intermediate. We suggest that PK depletion stimulates the activity of MondoA:MLX transcription factor heterodimers and subsequently, increases cellular TXNIP levels. TXNIP-mediated inhibition of thioredoxin (TXN) can reduce the ability of cells to scavenge reactive oxygen species (ROS) leading to the oxidative damage of cellular structures including DNA. These findings highlight an important regulatory axis affecting tumour suppression mechanisms and provide an attractive opportunity for combination cancer therapies targeting glycolytic activity and ROS-generating pathways
2023-07-06 | GSE235387 | GEO
Project description:To investigate the changes in circRNAs expression after SVA infection in PK-15 cells, we established a model of SVA-infected PK-15 cells.
2023-05-18 | GSE231770 | GEO
Project description:We hypothesized that the potential ability of the 18 kDa mitochondrial translocator protein (TSPO) to regulate gene expression may underlie its numerous reported functions, ranging from mitochondrial activity till mental disorders. Therefore, we applied microarray analysis of gene expression to U118MG glioblastoma cells. Within 1 hr the TSPO ligand PK 11195 induced changes in expression of immediate early genes and transcription factors. After 24 hrs primarily gene expression for enzymes and other proteins is changed. The associated gene products are known to affect various cellular functions: programmed cell death, cell cycle, viability, proliferation, migration, differentiation, development, tumorigenesis, and inflammatory / immune responses. Our microscopic studies showed intense TSPO mitochondrial labeling but no TSPO signal in the cell nuclei. Thus, it appears that the TSPO is part of the retrograde mitochondrial-nuclear signaling pathway for modulation of gene expression and thereby may exert its numerous effects on cell function, phenotype, and disease. U118MG cells (1.255 à 106) were seeded in Petri dishes (i.e. 28.5 à 103 cells / cm2) and allowed to proliferate for 3 days in full medium. Experiments for gene expression assayed with microarray typically consisted of three experimental groups and a vehicle control group (n = 3 for each group). Serum deprived medium was applied for 24 hrs, in the experimental groups ending with the inclusion a choice of various PK 11195 exposures i.e. either 1 hr, 3 hrs, or 24 hrs. Exposure to PK 11195 implies serum deprived medium with 1% alcohol (vehicle) and PK 11195 (25 µM final concentration) for the required time period. 25 µM of PK 11195 is the optimal concentration for these types of experiments with U118MG cells (Kugler et al., 2008). The cells were collected by trypsinization, washed by centrifugation in phosphate buffered saline (PBS) (400 à g, 5 min), and lysed [RLT lysis buffer provided with the RNeasy Mini Kit diluted with β-mercaptoethanol (1 : 100)], according to the manufacturer's instructions. Lysates were stored at -70oC.
2016-02-18 | E-GEOD-77998 | biostudies-arrayexpress