Cancer SLC3A2-mediated lysine uptake restricts T cell immunity against hepatocellular carcinoma
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE284633 | GEO | 2024/12/23
REPOSITORIES: GEO
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Project description:Among multiple interconnected pathways for L-Lysine (L-Lys) catabolism in pseudomonads, Pseudomonas aeruginosa PAO1 employed the decarboxylase and the transaminase pathways. However, up till now several genes involved in the operation and regulation of these pathways were still missing. Transcriptome analyses coupled with promoter activity measurements and mutant growth phenotype analysis lead us to identify several new members of the L-Lys and D-Lys catabolic pathways and their regulatory elements, including argR to trigger lysine decarboxylation into cadaverine, PauR for the γ-glutamylation pathway of polyamine catabolism into 5-aminovalerate, gcdR-gcdHG for glutarate utilization, dpkA, amaR-amaAB and PA2035 for D-Lys catabolism, lysR-lysXE for L-Lys efflux, and lysP for L-Lys uptake.
2015-12-09 | GSE75502 | GEO
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2024-10-17 | GSE272024 | GEO
Project description:Among multiple interconnected pathways for L-Lysine (L-Lys) catabolism in pseudomonads, Pseudomonas aeruginosa PAO1 employed the decarboxylase and the transaminase pathways. However, up till now several genes involved in the operation and regulation of these pathways were still missing. Transcriptome analyses coupled with promoter activity measurements and mutant growth phenotype analysis lead us to identify several new members of the L-Lys and D-Lys catabolic pathways and their regulatory elements, including argR to trigger lysine decarboxylation into cadaverine, PauR for the γ-glutamylation pathway of polyamine catabolism into 5-aminovalerate, gcdR-gcdHG for glutarate utilization, dpkA, amaR-amaAB and PA2035 for D-Lys catabolism, lysR-lysXE for L-Lys efflux, and lysP for L-Lys uptake. Gene expression microarray, including probe preparation, hybridization, fluidics run and chip scan, was performed by Georgia State University DNA/Protein Core Facility. P. aeruginosa PAO1 was grown aerobically in minimal medium P with 350 rpm shaking at 37C, in the presence of 10mM L-glutamate supplemented with 10 mM L-lysine, cadaverine, 5-amino valerate, glutaric acid, D-lysine or 5mM L-pipecolate. Cells were harvested when the optical density at 600 nm reached 0.5~0.6 by centrifugation for 5 minutes at 4C. Total RNA samples were isolated by RNeasy purification kit following instructions of the manufacturer (Qiagen). Reverse transcription for cDNA synthesis, fragmentation by DNase I treatment, cDNA probe labeling and hybridization were performed according to the instructions of GeneChip manufacturer (Affymetrix). Data were processed by Microarray Suite 5.0 software normalizing the absolute expression signal values of all chips to a target intensity of 500. GeneSpring software (Silicon Genetics) was used for expression pattern analysis and comparison. Data collection was carried out using GCOS 1.4 software (Affymetrix). Probe intensity values were normalized to a target value of 500 with normalization factor equal to 1. Data analysis was performed using GeneSpring GX 11 Software (Aglient, Palo Alto,CA). Related Research Papers: 1. Indurthi SM, Chou HT, Lu CD. Molecular Characterization of lysR-lysXE, gcdR-gcdHG, and amaR-amaAB Operons for Lysine Export and Catabolism: A Comprehensive Lysine Catabolic Network in Pseudomonas aeruginosa PAO1. Microbiology. 2015 Submitted [EMID:04803de65c782] 2. Chou HT, Li J, and Lu CD. Functional Characterization of the agtABCD and agtSR Operons for γ-Aminobutyrate and δ-Aminovalerate Uptake and Regulation in Pseudomonas aeruginosa PAO1. Curr. Microbiology. 2014 Jan;68(1):59-63. 3. Chou HT, Li JY, Peng YC, Lu CD. Molecular characterization of PauR and its role in control of putrescine and cadaverine catabolism through the γ-glutamylation pathway in Pseudomonas aeruginosa PAO1. J Bacteriol. 2013 Sep; 195(17):3906-13. 4. Chou HT, Hegazy M, Lu CD. L-lysine Catabolism is Controlled by Arginine/ArgR in Pseudomonas aeruginosa PAO1. J Bacteriol. 2010 Nov;192(22):5874-80
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Project description:Lenvatinib is the FDA-approved targeted drug for advanced hepatocellular carcinoma (HCC), but the efficacy is modest due to drug resistance. Tumor kinome re-wiring governs drug resistance in resistant cancer cells, which is an obstacle for efficient cancer therapy. Therefore, identification the kinases critical for this rewiring process in HCC is crucial.This study reveals the new role of CDK6 and its mechanistic insight in regulation of cancer stemness and drug resistance. These results support the combination treatment of lenvatinib with palbociclib for advanced HCC patients. Further studies will optimize patient target selection and identify the best treatment combinations.
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2014-04-17 | GSE55284 | GEO
Project description:Lenvatinib targets multiple oncogenic kinases including vascular endothelial growth factor receptors (VEGFRs) and showed longer median progression-free survival than sorafenib, the only approved treatment for >10 years. With the successful combination therapy of anti-PD-L1 pembrolizumab and anti-VEGF bevacizumab for advanced HCC as well as encouraging experimental findings, lenvatinib was also expected to enhance anti-tumor effects by combining anti-PD-1 pembrolizumab compared to lenvatinib alone; however, the phase III clinical trial failed to show their synergetic survival benefits, highlighting the need for elucidating its mode of action in human HCC specimens after lenvatinib treatment. We performed multi-layer transcriptome analyses of surgically resected human HCC samples after lenvatinib treatment as a neo-adjuvant therapy using RNA-sequencing. Molecular pathway analyses and immunohistochemistry revealed that VEGF-mediated aberrant vascularity and cytotoxic GZMK+CD8 T cells infiltration were significantly improved in lenvatinib-treated HCC; however, the majority of these cytotoxic T cells were trapped in the intratumor fibrotic stroma, suggesting that lenvatinib-treated HCC is in the so-called excluded condition. Excluded tumors are generally believed to be less responsive to immune checkpoint inhibitors, which might be the reason the combination therapy failed to show the additive benefits.
2023-08-08 | GSE223201 | GEO
Project description:In undifferentiated human ES cells, 48hr Leucine deprivation (delta Leu) or Lysine deprivation (delta Lys) led to apoptosis. We used microarrays to detail the mollecular mechanism of cell-death caused by Leu, Lys deprivation in undifferentiated ES cells. Cells were harvested at undifferentiated stages for RNA extraction and hybridization on Affymetrix microarrays. We performed gene expression profiles of undifferentiated khES3 cells cultured in complete (comple),Leu or Lys deprivation for 5 hr.
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Project description:Protein lysine acetylation is a vital post-translational modification (PTM) that plays important roles in biological processes and human diseases. However, its potential roles in hepatocellular carcinoma (HCC) development remain largely unknown. Here we performed a quantitative acetylome analysis of tumor and normal liver tissues from HCC patients. Overall, we identified 792 lysine acetylation sites in 415 proteins, and almost half of their acetylation levels were significantly changed in HCC tumor tissues. The acetylated proteins mainly consisted of metabolic enzymes, which was consistent with the subcellular location analysis that they were primarily located in mitochondria and cytoplasm. Consistently, Bioinformatics analysis showed that differently acetylated proteins were mainly involved in metabolic pathways, such as glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid oxidation, and glutamine metabolism. Then we selected two down-regulated enzymes and verified their acetylation levels in HCC liver tissues. In addition, transcription factors and proteins associated with oxidative stress were identified with aberrant acetylation levels in HCC tumor tissues. Our findings illustrate abundant lysine acetylation sites in HCC liver tissues, which provides insight into the role of lysine acetylation in HCC development, and further contributes to possible implications for its use in diagnose and therapy in the future.
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