Integrated Bioinformatics Analysis Identified ASNS and DDIT3 as the Therapeutic Target in Castrate-Resistant Prostate Cancer

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(5), P. 2836 - 2836

Published: Feb. 29, 2024

Many studies have demonstrated the mechanisms of progression to castration-resistant prostate cancer (CRPC) and novel strategies for its treatment. Despite these advances, molecular underlying CRPC remain unclear, currently, no effective treatments are available. Here, we characterized key genes involved in gain insight into potential therapeutic targets. Bicalutamide-resistant cells derived from LNCaP were generated named Bical R. RNA sequencing was used identify differentially expressed (DEGs) between In total, 631 DEGs (302 upregulated 329 downregulated genes) identified. The Cytohubba plug-in Cytoscape seven hub (ASNS, AGT, ATF3, ATF4, DDIT3, EFNA5, VEGFA) associated with progression. Among genes, ASNS DDIT3 markedly cell lines patient samples. patients high expression showed worse disease-free survival Cancer Genome Atlas (TCGA)-prostate adenocarcinoma (PRAD) datasets. Our study revealed a association CRPC. These results may contribute development targets progression, aiming improve clinical efficacy

Language: Английский

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Transfer learning of multicellular organization via single-cell and spatial transcriptomics

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 3, 2024

ABSTRACT Spatial tissues exhibit complex gene expression and multicellular patterns that are difficult to dissect. Single-cell RNA sequencing (scRNA-seq) provides full coverages of genes, but lacking spatial information, whereas transcriptomics (ST) measures locations individual or group cells, with more restrictions on information. To integrate scRNA-seq ST data, we introduce a transfer learning method decipher organization cells named iSORT. iSORT trains neural network maps expressions using data along slices as references. can find at single-cell scale, identify key genes drive the patterning, infer pseudo-growth trajectories concept SpaRNA velocity. Benchmarking simulation comparing multiple existing tools show iSORT’s robustness accuracy in reconstructing organization. Using our own new human artery datasets, shows its capability dissecting atherosclerosis. Applications range biological systems, such mouse embryo, brain, Drosophila developmental heart, demonstrate utilize both datasets uncover multilayer information single cells.

Language: Английский

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Aerobic glycolysis but not GLS1-dependent glutamine metabolism is critical for anti-tumor immunity and response to checkpoint inhibition

Cell Reports, Journal Year: 2024, Volume and Issue: 43(8), P. 114632 - 114632

Published: Aug. 1, 2024

Tumor cells undergo uncontrolled proliferation driven by enhanced anabolic metabolism including glycolysis and glutaminolysis. Targeting these pathways to inhibit cancer growth is a strategy for treatment. Critically, however, tumor-responsive T share metabolic features with cells, making them susceptible treatments as well. Here, we assess the impact on anti-tumor cell immunity exhaustion genetic ablation of lactate dehydrogenase A (LDHA) glutaminase1 (GLS1), key enzymes in aerobic Loss LDHA severely impairs expansion response tumors chronic infection. In contrast, lacking GLS1 can compensate impaired glutaminolysis engaging alternative pathways, upregulation asparagine synthetase, thus efficiently respond tumor challenge infection well immune checkpoint blockade. GLS1-dependent glutaminolysis, but not glycolysis, may therefore be successful treatment, particularly combination immunotherapy.

Language: Английский

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Analysis and functional relevance of the chaperone TRAP-1 interactome in the metabolic regulation and mitochondrial integrity of cancer cells

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: May 10, 2023

Abstract The 90 kDa heat shock protein, Hsp90, functions as a cancer chaperone contributing to tumor proliferation. We have encountered the mitochondrial homolog of TRAP-1, regulating dynamics, metabolism, and metastasis. Although Hsp90 is associated with broad network proteins various cellular processes, TRAP-1-mediated networks are unclear. Therefore, using TRAP-1 knockdown (KD) overexpression (OE) systems, we compared their quantitative transcriptome (RNA Sequencing) proteomic (LC–MS/MS) patterns obtain molecular signatures that altered in response KD or OE. report modulating vital metabolic pathways such tricarboxylic acid cycle, oxidative phosphorylation, electron transport chain, glycolysis, gluconeogenesis. In addition, facilitated pentose phosphate pathway shunt carbons back glycolysis gluconeogenesis, much-solicited response. Subsequently, examined interactome tandem affinity purification system identified 255 unique proteins. These diverse appear regulate several including energy suggesting addition rewiring, maintains integrity. Our study exposes unknown cells. Systematic evaluation interactors may uncover novel regulatory mechanisms disease aggression. Since inhibitors emerging potential anticancer agents, our gains importance.

Language: Английский

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Asparagine availability controls B cell homeostasis

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: April 5, 2023

Abstract Germinal centre (GC) B cells proliferate at some of the highest rates any mammalian cell, yet metabolic processes which enable this are poorly understood. We performed integrated metabolomic and transcriptomic profiling GC cells, found that metabolism non-essential amino acid asparagine (Asn) was highly upregulated. Asn conditionally essential to its synthetic enzyme, synthetase (ASNS) upregulated following their activation, particularly more markedly in absence Asn, through stress response sensor general control non-derepressible 2 (GCN2). When Asns is deleted cell survival proliferation low conditions were strongly impaired, removal environmental by asparaginase or dietary restriction compromised reaction, impairing affinity maturation humoral influenza infection. Using stable isotope tracing single RNA sequencing, we adaptation requires ASNS, oxidative phosphorylation, mitochondrial homeostasis, synthesis nucleotides sensitive deprivation. Altogether, reveal acts as a key regulator function homeostasis. The one sentence summary Asparagine critical function, maintaining germinal reaction.

Language: Английский

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