Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis
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PROVIDER: PRJNA1218217 | ENA |
REPOSITORIES: ENA
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Project description:Nutrient limitation in the microenvironment of poorly perfused tumors constrains the metabolism of cancer cells. Identifying these microenvironmental constraints can provide new insight into the nutritional biochemistry of tumors and reveal metabolic liabilities of cancer cells. We have found that limitation of arginine in pancreatic cancers inhibits fatty acid synthesis by suppressing the lipogenic transcription factor SREBP1. SREBP1-driven fatty acid synthesis produces saturated and monounsaturated fatty acids. Producing these fatty acids enables cells to maintain a balance of differently saturated fatty acids needed for lipid homeostasis, even upon exposure to environments enriched in one specific class of fatty acids. Given the constraints on lipid synthesis in the microenvironment, we asked if pancreatic cancers are sensitive to exposure to fats with imbalanced levels of saturated and unsaturated fats. We found microenvironmental constraints on lipid synthesis sensitize pancreatic cancer cells and tumors to exposure to fat sources that are enriched in polyunsaturated fatty acids. Thus, amino acid restriction in the tumor microenvironment constrains lipid metabolism in pancreatic cancer, which renders pancreatic tumors incapable of maintaining lipid homeostasis upon exposure to polyunsaturated-enriched fats.
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Project description:The purpose of this research study is to understand the effects of oral aspirin taken daily with an arginine-restricted diet on certain colorectal cancer biomarkers in treated colorectal cancer patients. Patients with colorectal cancer are at high risk for recurrence and for development of secondary colorectal cancers in the future. Specific chemicals (polyamines, prostaglandins) in the body referred to as biomarkers can be measured to help understand a person’s risk for developing colorectal cancer. Specific biomarkers associated with colorectal cancer have been identified in prior laboratory studies. By measuring these predefined biomarkers before and after the study intervention, we can assess how they are affected by the intervention, and gain knowledge about their usefulness in colorectal cancer patients on clinical trial.
This study is a Phase IIa clinical biomarker study, using oral aspirin 325 mg taken daily with an arginine-restricted diet designed to reduce arginine intake by at least 30% during the 12-week study period. The biomarkers will be obtained from patient by performing endoscopy (a procedure used to look at the inside of the bowel, rectum and colon) and biopsy (taking samples of tissue), phlebotomy (drawing blood), and urine collection. Biopsies are done to evaluate changes in tissue content that may relate to early events in colon cancer formation. This was the procedure used to diagnose your condition initially. There will be 24 patients enrolled into this study performed through University of California Irvine Medical Center.
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Project description:Our previous work has indicated that extracellular arginine concentrations may be an important stimulus for gene regulation in S gordonii. Here cells were cultured in a chemically defined medium (CDM) to mid exponential phase . Cultures were split and resuspended in either CDM or CDM lacking arginine. After 30 mins RNA was extracted and gene expression was monitored using an Agilent microarray.
2015-10-01 | GSE51346 | GEO
Project description:Staphylococcus aureus is responsible for a substantial number of invasive infections globally each year. These infections are problematic because they are frequently recalcitrant to antibiotic treatment. Antibiotic tolerance, the ability of bacteria to persist despite normally lethal doses of antibiotics, contributes to antibiotic treatment failure in S. aureus infections. To understand how antibiotic tolerance is induced, S. aureus biofilms exposed to multiple anti-staphylococcal antibiotics were examined using both quantitative proteomics and transposon sequencing. These screens indicated that arginine metabolism is involved in antibiotic tolerance within a biofilm and led to the hypothesis that depletion of arginine within S. aureus communities can induce antibiotic tolerance. Consistent with this hypothesis, inactivation of argH, the final gene in the arginine synthesis pathway, induces antibiotic tolerance. Arginine restriction was found to induce antibiotic tolerance via inhibition of protein synthesis. In a mouse skin infection model, an argH mutant has enhanced ability to survive antibiotic treatment with vancomycin, highlighting the relationship between arginine metabolism and antibiotic tolerance during S. aureus infection. Uncovering this link between arginine metabolism and antibiotic tolerance has the potential to open new therapeutic avenues targeting previously recalcitrant S. aureus infections.
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Project description:We report a conserved transcriptomic signature of reduced fatty acid and lipid metabolism gene expression in human post-mortem ALS spinal cord and a Drosophila model of the most common genetic cause of FTD/ALS, a repeat expansion in C9orf72. To investigate lipid alterations, we performed lipidomics on C9FTD/ALS iPSC-neurons and post-mortem FTLD brain tissue. This revealed a common and specific reduction in phospholipid species containing polyunsaturated fatty acids (PUFAs). To determine whether this PUFA deficit contributes to neurodegeneration, we fed C9FTD/ALS flies PUFAs, which yielded a modest increase in survival. However, increasing PUFA levels specifically in neurons of the C9orf72 flies, by overexpressing fatty acid desaturase enzymes, led to a substantial extension of lifespan. Neuronal overexpression of fatty acid desaturases also suppressed stressor induced neuronal death in C9FTD/ALS patient iPSC-neurons. These data implicate neuronal fatty acid saturation in the pathogenesis of FTD/ALS and suggest that interventions to increase PUFA levels specifically within neurons will be beneficial.
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Project description:In the present study, we investigated the consequences of n-3 polyunsaturated fatty acids (PUFA) depletion on hepatic lipid metabolism in mice fed during three months with a diet presenting a high n-6/n-3 PUFA ratio to induce n-3 PUFA depletion. Microarray analyses were performed to identify the molecular targets involved in the development of hepatic steatosis associated with n-3 PUFA depletion.
2011-08-26 | GSE26986 | GEO
Project description:BRD4 functions as an epigenetic reader and plays a crucial role in regulating transcription and genome stability. Dysregulation of BRD4 is frequently observed in various human cancers. However, the molecular details of BRD4 regulation remain largely unknown. Here, we report that PRMT2- and PRMT4-mediated arginine methylation is pivotal for BRD4-dependent transcription, DNA repair, and tumor growth. Specifically, PRMT2/4 interact with and methylates BRD4 at R179, R181, and R183. This arginine methylation selectively controls a transcriptional program by promoting BRD4 enrichment at the hyper-acetylated chromatin regions. Moreover, BRD4 arginine methylation is induced by DNA damage and thereby promotes its binding to chromatin for DNA repair. Deficiency in BRD4 arginine methylation significantly suppresses tumor growth and sensitizes cells to BET inhibitors and DNA damaging agents. Therefore, our findings reveal an arginine methylation-dependent regulatory mechanism of BRD4 function and highlight targeting PRMT2/4 for better anti-tumor effect of BET inhibitors and DNA damaging agents.
2022-12-14 | GSE206667 | GEO
Project description:Staphylococcus aureus is responsible for a substantial number of invasive infections globally each year. These infections are problematic because they are frequently recalcitrant to antibiotic treatment. Antibiotic tolerance, the ability of bacteria to persist despite normally lethal doses of antibiotics, contributes to antibiotic treatment failure in S. aureus infections. To understand how antibiotic tolerance is induced, S. aureus biofilms exposed to multiple anti-staphylococcal antibiotics were examined using both quantitative proteomics and transposon sequencing. These screens indicated that arginine metabolism is involved in antibiotic tolerance within a biofilm and led to the hypothesis that depletion of arginine within S. aureus communities can induce antibiotic tolerance. Consistent with this hypothesis, inactivation of argH, the final gene in the arginine synthesis pathway, induces antibiotic tolerance. Arginine restriction was found to induce antibiotic tolerance via inhibition of protein synthesis. In murine skin and bone infection models, an argH mutant has enhanced ability to survive antibiotic treatment with vancomycin, highlighting the relationship between arginine metabolism and antibiotic tolerance during S. aureus infection. Uncovering this link between arginine metabolism and antibiotic tolerance has the potential to open new therapeutic avenues targeting previously recalcitrant S. aureus infections.
2024-07-11 | PXD052440 | Pride
Project description:Restriction of Arginine Induces Antibiotic Tolerance in Staphylococcus aureus
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