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

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

PROVIDER: PRJNA901484 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22284506_1.fastq.gz	Fastqsanger.gz
	SRR22284506_2.fastq.gz	Fastqsanger.gz
	SRR22284507_1.fastq.gz	Fastqsanger.gz
	SRR22284507_2.fastq.gz	Fastqsanger.gz
	SRR22284508_1.fastq.gz	Fastqsanger.gz

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

Project description: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

2023-12-12 | GSE217965 | GEO

Heme-Nrf2 signaling shifts myeloid differentiation

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Lung macrophages mediate helminth resistance through differential activation of recruited monocyte-derived alveolar macrophages and arginine depletion

Project description:Lung macrophages mediate helminth resistance through differential activation of recruited monocyte-derived alveolar macrophages and arginine depletion

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Heme-Nrf2 signaling shifts myeloid differentiation

Project description:Heme is an erythrocyte-derived toxin that drives disease progression in hemolytic anemias. During hemolysis, specialized bone marrow-derived macrophages with a high heme-metabolism capacity orchestrate disease adaptation by removing damaged erythrocytes and heme-protein complexes from the blood and supporting iron recycling for erythropoiesis. Here, we performed single-cell RNA sequencing with RNA velocity analysis of GM-CSF-supplemented mouse bone marrow cultures to assess myeloid differentiation under heme stress. We found that heme-activated NRF2 signaling shifted the differentiation trajectories of cells towards antioxidant, iron-recycling macrophages at the expense of dendritic cells, as these cells were selectively deficient in heme-exposed bone marrow cultures. Heme eliminated the capacity of GM-CSF-supplemented bone marrow cultures to activate antigen-specific T cells. The generation of functionally competent dendritic cells was restored by NRF2 loss. The heme-induced phenotype was reproduced in hemolytic mice with sickle cell disease and spherocytosis and associated with reduced dendritic cell functions in the spleen. Our data provide a novel mechanistic underpinning how hemolytic stress may provoke hyposplenism-related secondary immunodeficiency, which is a critical determinant of mortality in patients with genetic hemolytic anemias.

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Nrf2 transcript alterations

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Comparison of the transcriptomic impact of NRF2 depletion with that of NUAK1 depletion in SW480 colorectal cancer cells

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Arginine methylation regulates widespread alternative polyadenylation

Project description:Alternative polyadenylation (APA) has recently been recognized as a universal mechanism for gene regulation, but it remains unclear how APA is controlled. Here we report that the Arabidopsis thaliana Protein Arginine Methyltransferase 10 (AtPRMT10) regulates global APA with its protein partner HLP1, a conserved hnRNP A/B protein. HLP1 binds preferentially to A-rich and U-rich cis-elements around polyadenylation sites, thereby linking AtPRMT10 to the control of APA through protein-protein interactions. AtPRMT10 mutations cause significant proximal-to-distal poly(A) site shifts largely overlapping with those in hlp1-1 mutants. Proximal polyadenylation is maintained by AtPRMT10-directed methylation and is mediated in part by methylation of HLP1 at specific arginine residues. Our findings demonstrate that arginine methylation of an RNA-binding protein adds a novel layer of regulation to widespread alternative polyadenylation.

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Loss of LUC7L2 and U1 snRNP subunits shifts energy metabolism from glycolysis to OXPHOS

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