Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Depletion of Nrf2 in pancreatic cancer cells shifts arginine metabolism into the phosphocreatine energy system

ABSTRACT: Depletion of Nrf2 leads to an increase in cellular ROS, reduced glutathione and thiols, and profound reprogramming of metabolism. Unbiased transcriptome analyses show that key enzymes of glycolysis, pentose phosphate pathway, and glutathione cycle are significantly downregulated, while enzymes of arginine and medium-chain fatty acids metabolism are upregulated. Besides glutamine, pancreatic cancer cells deficient of Nrf2 axis become highly dependent on arginine, which is channelled into the synthesis of phosphocreatine and polyamines. Key enzymes of the creatine pathway, gatm and ckb, are more expressed and more active in Nrf2(-/-) than in WT cells. This metabolism shift creates an energy buffer that enables pancreatic cancer cells to handle increased energy demand. Metabolomic analysis showed that 12% of the creatine pool is phosphorylated in Nrf2(-/-) cells, while the level drops to < 0.1% in WT cells. The inhibition of the creatine pathway with cyclocreatine in Nrf2(-/-) cells, reduces by 43% the ATP level and by 70% invasion rate in matrigel. Furthermore, we found that combination therapies that can target simultaneously the creatine pathway and the KRAS G12D-Nrf2 axis produce a stronger anticancer effect than monotherapies. Taken together, our data provide the basis for the rationale design of new combination therapies against pancreatic cancer. The KRAS G12D-Nrf2 axis controls redox homeostasis and metabolism in PDAC cells. Suppression of KRAS G12D-Nrf2 decreases glycolysis, PPP and glutathione cycle and promotes a metabolic shift of arginine into the synthesis of phosphocreatine

ORGANISM(S): Homo sapiens

PROVIDER: GSE217965 | GEO | 2023/12/12

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation

Project description:Oncogenic mutations in tumor cells regulate signaling both within tumor cells and heterotypic stromal cells. However, whether oncogenes regulate tumor cell signaling via stromal cells is poorly understood. Here we show that oncogenic KRAS (KRAS-G12D) uniquely regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with phosphoproteomic multiplexing we conducted a multivariate analysis of heterocellular KRAS-G12D signaling in Pancreatic Ductal Adenocarcinoma (PDA) cells. By engaging heterotypic fibroblasts, KRAS-G12D drives unique reciprocal signaling in tumor cells to employ additional kinases and double the number of regulated signaling nodes from cell-autonomous KRAS-G12D. Heterocellular signaling produces a distinct tumor cell phosphoproteome, total proteome, and increase mitochondria capacity via an IGF1R/AXL-AKT axis. Reciprocal KRAS-G12D phenotypes require a heterocellular context and are unreachable by cell-autonomous KRAS-G12D alone. These results demonstrate oncogene signaling should be viewed as a heterocellular process and our existing homocellular perspective underrepresents the extent of oncogene signaling in cancer.

2016-04-19 | PXD003223 | Pride

Increased phosphocreatine/creatine ratio in white adipocytes promotes inflammation

Project description:The mechanisms promoting disturbed white adipocyte function in obesity remain largely unclear. Herein, we integrate white adipose tissue (WAT) metabolomic and transcriptomic data from clinical cohorts and find that the WAT phosphocreatine/creatine ratio is increased and creatine kinase-B expression and activity is decreased in the obese state. . In human in vitro and murine in vivo models, we demonstrate that decreased phosphocreatine metabolism in white adipocytes alters AMPK activity via effects on ATP/ADP levels, independently of WAT beigeing. This disturbance promotes a pro-inflammatory profile characterized, in part, by increased CCL2 production. These data suggest that the phosphocreatine/creatine system links cellular energy shuttling with pro-inflammatory responses in human and murine white adipocytes. Our findings provide unexpected perspectives on the mechanisms driving WAT inflammation in obesity and may present avenues to target adipocyte dysfunction.

2022-01-27 | GSE192361 | GEO

Kras-induced ikk2/nf-kappaB activation by IL-1 alpha and p62 freedforward loops is required for development of pancreatic ductal adenocarcinoma

Project description:This SuperSeries is composed of the following subset Series: GSE27478: Gene expression differences between the pancreatic tissues of Pdx1-Cre;KrasLSL-G12D and Pdx1-Cre;KrasLSL-G12D;IKK2/betaF/F mice GSE33322: Gene expression analysis between the pancreatic tissues of Pdx1-cre;Kras LSL-G12D and Pdx-cre;KrasLSL-G12D;IKK2/beta F/F mice Refer to individual Series

2012-01-24 | E-GEOD-33323 | biostudies-arrayexpress

Gene expression analysis between the pancreatic tissues of Pdx1-cre;Kras LSL-G12D and Pdx-cre;KrasLSL-G12D;IKK2/beta F/F mice

Project description:Constitutive Kras and NF-kB activation is identified as signature alterations in human pancreatic ductal adenocarcinoma (PDAC). Here, we report that pancreas-targeted IKK2/beta inactivation inhibited NF-kB activation and completely suppressed PDAC development. Our findings demonstrated that NF-kB is required for development of pancreatic ductal adenocarcinoma that was initiated by Kras activation. Pancreatic tissue from 4 groups of mice were used in this project: (1) the pancreas normal appearance of Pdx1-cre;KrasLSL-G12D;IKK2/beta mice, (2) the normal pancreas of Pdx1-cre;KrasLSL-G12D mice, (3) the pancreatic lesion of pancreatic intraepithelial neoplasia (PanIN) of Pdx1-cre;KrasLSL-G12D mice, and (4) the pancreatic lesion of PDAC of Pdx1-cre;KrasLSL-G12D mice. Each group included three mice. RNA samples from mouse pancreas were hybridized on GeneChip Mouse Gene 1.0 ST arrays (Affymetrix). Group (1) and group (2) were compared, and group (2), group (3) and group (4) were compared.

2012-01-24 | E-GEOD-33322 | biostudies-arrayexpress

Disruption of STAT3 signaling promotes KRAS induced lung tumorigenesis

Project description:Oncogenic STAT3 functions are known in various malignancies. We found that STAT3 plays an unexpected tumor suppressive role in KRAS-mutant non-small-cell-lung cancer (NSCLC). In mice, tissue-specific inactivation of Stat3 resulted in increased Kras (G12D)-driven NSCLC initiation and malignant progression leading to markedly reduced survival. Clinically, low STAT3 expression levels correlate with poor survival in human lung adenocarcinoma patients with smoking history. Consistently, KRAS-mutant lung tumors showed reduced STAT3 levels. Mechanistically, we show that STAT3 controls NFÎºB-induced IL-8-expression by sequestering NFÎºB in the cytoplasm while IL-8 in turn regulates myeloid tumor infiltration and tumor vascularization thereby promoting tumor progression. These results identify a novel STAT3-NFÎºB-IL-8 axis in KRAS-mutant NSCLC with therapeutic and prognostic relevance WT: Control lung; KRAS: Lung tumors expressing KRAS G12D; KRAS STAT3 KO: Lung tumors expressing KRAS G12D- STAT3 deficient; tumors of four mice pooled per sample

2015-02-05 | E-GEOD-52798 | biostudies-arrayexpress

Characterization of a mitochondria associated phosphocreatine phosphatase in thermogenic adipocytes

Project description:Adaptive thermogenesis has attracted much attention because of its ability to raise systemic energy expenditure and counter obesity and diabetes. Recent data have indicated that thermogenic fat cells utilize creatine to stimulate futile substrate cycling, dissipating chemical energy as heat. This model was based on the super-stoichiometric relationship between creatine added to mitochondria and O2 consumed, and this project aims at providing direct evidence for the molecular basis of this futile creatine cycling activity. In this project, we found that thermogenic fat cells contain robust phosphocreatine hydrolase (PCr’ase) activity, attributable to tissue-nonspecific alkaline phosphatase (TNAP), which was identified by the quantitative mass spectrometric analysis of a purified mitochondrial protein fraction containing the PCr’ase activity. TNAP hydrolyzes phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation; it is localized to mitochondria of thermogenic fat cells, where the futile creatine cycling occurs. Furthermore, we demonstrated in this project the essential role of TNAP in activating the futile creatine cycling and increasing whole body energy expenditure using genetic and pharmacological approaches. We also found that the genetic depletion of TNAP in murine adipose tissue causes rapid-onset obesity, with no change in movement or feeding behavior of the animals. Using quantitative mass spectrometry, we showed that genetic depletion of TNAP causes an upregulation of UCP1, as well as other proteins involved in oxidative metabolism, to compensate for a dampened thermogenesis. In summary, the data we acquired in this project illustrate the critical role of TNAP as a phosphocreatine phosphatase in the futile creatine cycling and adipose thermogenesis.

2022-02-17 | PXD025032 | Pride

Oncogenic Mutations of KRAS Modulate Its Turnover by the CUL3/LZTR1 E3 ligase Complex

Project description:KRAS is a proto-oncogene encoding a small GTPase. Mutations contribute up to 30% of human solid tumours including lung adenocarcinoma, pancreatic and colorectal carcinomas. Most KRAS activating mutations interfere with GTP hydrolysis, essential for its role as a molecular switch, leading to alterations in their molecular environment and oncogenic signalling. Here, APEX-2 proximity labelling was used to profile the molecular environment of wild type and G12D, G13D and Q61H activating mutants of KRAS under both, starvation and stimulation conditions. We demonstrate by quantitative proteomics the presence of known interactors of KRAS including a-RAF and LZTR1, which varied in abundance with wildtype and KRAS mutants. Notably, the KRAS mutations G12D, G13D and Q61H abrogate association with LZTR1. Wildtype KRAS and LZTR1, as part of the CUL3 ubiquitin E3 ligase complex, affect each other’s protein stability.

2024-03-06 | PXD029725 | Pride

Single cell RNA sequencing profiles on whole tumors from a Kras/Rnf43 genetically engineered mouse model of pancreatic adenocarcinoma

Project description:We report single cell RNA sequencing of pancreatic enzymatically digested whole, fresh tumors from a genetically engineered mouse model (GEMM) of pancreatic adenocarcinoma. This GEMM consists of pancreas specific expression of oncogenic Kras (Kras-G12D) in addition of homozygous deletion of the ring finger domain (catalytic domain) of Rnf43. This GEMM is termed 'KRC'.

2022-03-23 | GSE188946 | GEO

The Gustatory Sensory G-Protein GNAT3 Suppresses Pancreatic Cancer Progression in Mice

Project description:Ablation of the gustatory G-protein, GNAT3, in damage and KRAS G12D induced pancreatic transformation enhanced CXCL1 and CXCL2 expression, altered the immunoregulatory gene expression of CXCR2 expressing myeloid-derived suppressor cells, and increased gMDSC presence to promote the progression of metastatic pancreatic ductal adenocarcinoma.

2021-04-21 | GSE149165 | GEO

A Genetic-to-Epigenetic Crosstalk Plays a Pivotal Role in the Promotion of KrasG12D-Induced Senescence and PanIN formation

Project description:Nupr1 is a chromatin protein which cooperates with KrasG12D to induce PanIN formation in mice, though the molecular mechanisms underlying this effect remain to be fully characterized. In the current study, we find that Nupr1 acts as a gene modifier of the effect of KrasG12D-induced senescence by regulating Dnmt1 expression, changing the genome-wide levels of DNA methylation and activating the growth regulatory FoxO3a-Skp2-p27Kip1-pRb-E2F pathway. Congruently, 5-aza-2'-deoxycytydine, a general inhibitor of DNA methylation, reverses the KrasG12D-induced PanIN development through an effect on oncogene-induced senescence. Therefore, mechanistically this data reveals that epigenetic events modulate the functional outcome of genetic mutations during the progression of pancreatic cancer. The fact that small drug inhibitors of these epigenetic pathways reverse the effects triggered by genetic changes lends significant biomedical relevance to this knowledge for the future design of novel therapies aimed at controlling the progression of pancreatic cancer. The pancreatic gene expression profile of Nupr1 (+/+) Kras-G12D mouse was compared to the Nupr1 (-/-) Kras-G12D mouse.

2013-07-01 | E-GEOD-45232 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data