Inhibition of Acyl-CoA Synthetase Long Chain (ACSL) Isozymes Decreases Multiple Myeloma Cell Proliferation, Mitochondrial Function and Affects Key Survival Pathways
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ABSTRACT:
PROVIDER: PRJNA1063258 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27482036_1.fastq.gz | Fastqsanger.gz | |||
| SRR27482036_2.fastq.gz | Fastqsanger.gz | |||
| SRR27482037_1.fastq.gz | Fastqsanger.gz | |||
| SRR27482037_2.fastq.gz | Fastqsanger.gz | |||
| SRR27482038_1.fastq.gz | Fastqsanger.gz |
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Project description:Multiple myeloma (MM) is an incurable cancer of plasma cells that will cause ~12,590 deaths in the USA in 2023. Dysregulation of fatty acid (FA) metabolism is associated with MM development and progression but the underlying mechanisms remains unknown. The acyl-CoA synthetase long-chain family members (ACSLs) convert free long-chain fatty acids into fatty acyl-CoA esters, and play a key role in catabolic and anabolic fatty acid metabolism. Cancer Dependency Map data suggested that ACSL4 and ACSL3 are among the top 25% Hallmark Fatty Acid Metabolism genes that support MM fitness. Here, we show inhibition of the ACSLs in human myeloma cell lines using the pharmacological inhibitor Triascin C (TriC) caused apoptosis, and decreased proliferation in a dose- and time-dependent manner. As KRAS mutants are the most common mutation among MM patients, we used MM.1S cells to study the mechanisms of TriC toxicity. RNA-seq of MM.1S cells treated with 1.00 μM TriC for 24 hours had gene expression profiles significantly enriched in apoptosis, ferroptosis, and ER stress compared to vehicle treated cells. Proteomics of MM.1S cells treated with either 1.00 μM or 2.00 μM TriC for 48 hours revealed that mitochondrial dysfunction and oxidative phosphorylation were significantly enriched pathways of interest relative to vehicle treated cells. Indeed, metabolic flux analysis showed MM.1S cells treated with TriC after 24 hours had decreased mitochondrial ATP production rate. Flow cytometric analyses revealed concomitant decreases in number and mitochondrial membrane potential, and increases in mitochondrial superoxide. Implications: Overall, our data support the hypothesis that suppression of ACSL in human MM cells inhibited their growth and viability, potentially indicating that ACSL proteins may be promising therapeutic targets in treating myeloma progression.
2024-12-03 | GSE252929 | GEO
Project description:Multiple myeloma (MM) is an incurable cancer of plasma cells that will cause ~12,590 deaths in the USA in 2023. Dysregulation of fatty acid (FA) metabolism is associated with MM development and progression but the underlying mechanisms remain unknown. The acyl-CoA synthetase long-chain family members (ACSLs) convert free long-chain fatty acids into fatty acyl-CoA esters, and play a key role in catabolic and anabolic fatty acid metabolism. Cancer Dependency Map data suggested that ACSL4 and ACSL3 are among the top 25% Hallmark Fatty Acid Metabolism genes that support MM fitness. Here, we show inhibition of the ACSLs in human myeloma cell lines using the pharmacological inhibitor Triascin C (TriC) caused apoptosis, and decreased proliferation in a dose- and time-dependent manner. As KRAS mutants are the most common mutation among MM patients, we used MM.1S cells to study the mechanisms of TriC toxicity. RNA-seq of MM.1S cells treated with TriC for 24 hours had transcriptomes significantly enriched in apoptosis, ferroptosis, and ER stress. Proteomics of MM.1S cells treated with TriC for 48 hours revealed that mitochondrial dysfunction and oxidative phosphorylation were significantly enriched pathways of interest. Indeed, metabolic flux analysis showed MM.1S cells treated with TriC after 24 hours had decreased mitochondrial ATP production rates. Flow cytometric analyses revealed decreases in mitochondrial number and membrane potential with increased mitochondrial superoxide levels. Implications: Overall, our data support the hypothesis that suppression of ACSL in human MM cells inhibited their growth and viability, potentially indicating that ACSL proteins may be promising therapeutic targets in treating myeloma progression.
2025-06-16 | PXD049304 | Pride
Project description:Acyl-coA Binding Protein neutralization improves cancer immunosurveillance
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Project description:Floodings already have a nearly 60% share in the worldwide damage to crops provoked by natural disasters. Climate change will cause plants to be even more frequently exposed to oxygen limiting conditions (hypoxia) in the near future due to heavy precipitation and concomitant waterlogging or flooding events in large areas of the world. Although the homeostatic regulation of adaptive responses to low oxygen stress in plants is well described, it remained unknown by which initial trigger the molecular response to low-oxygen stress is activated. Here, we show that a hypoxia-induced decline of the ATP level of the cell reduces LONG-CHAIN ACYL-COA SYNTHETASE (LACS) activity, which leads to a shift in the composition of the acyl-CoA pool. High oleoyl-CoA levels release the transcription factor RELATED TO APETALA 2.12 (RAP2.12) from its interaction partner ACYL-COA BINDING PROTEIN (ACBP) at the plasma membrane to induce low oxygen-specific gene expression. We show that different acyl-CoAs provoke unique molecular responses revealing a novel role as cellular signalling component also in plants. In terms of hypoxia signalling, dynamic acyl-CoA levels integrate the cellular energy status into the oxygen signalling cascade with ACBP and RAP2.12 being the central hub. The conserved nature of the ACBP:RAP2.12 module in crops and the novel mechanistic understanding of how low-oxygen stress responses are initiated by oleoyl-CoA in plants provide useful leads for enhancing future food security.
2018-04-30 | GSE97186 | GEO
Project description:Multiple myeloma (MM) is an incurable cancer of plasma cells with a 5-year survival rate of 59%. Dysregulation of fatty acid (FA) metabolism is associated with MM development and progression; however, the underlying mechanisms remain unclear. Acyl-CoA synthetase long-chain family members (ACSLs) convert free long-chain fatty acids into fatty acyl-CoA esters and play key roles in catabolic and anabolic fatty acid metabolism. The Cancer Dependency Map data suggested that ACSL3 and ACSL4 were among the top 25% Hallmark Fatty Acid Metabolism genes that support MM fitness. Here, we show that inhibition of ACSLs in human myeloma cell lines using the pharmacological inhibitor Triascin C (TriC) causes apoptosis and decreases proliferation in a dose- and time-dependent manner. RNA-seq of MM.1S cells treated with TriC for 24 h showed a significant enrichment in apoptosis, ferroptosis, and ER stress. Proteomics of MM.1S cells treated with TriC for 48 h revealed that mitochondrial dysfunction and oxidative phosphorylation were significantly enriched pathways of interest, consistent with our observations of decreased mitochondrial membrane potential and increased mitochondrial superoxide levels. Interestingly, MM.1S cells treated with TriC for 24 h also showed decreased mitochondrial ATP production rates and overall lower cellular respiration.
| S-EPMC10979990 | biostudies-literature
Project description:The mechanisms underlying the formation of acyl protein modifications remain poorly understood. By investigating the reactivity of endogenous acyl-CoA metabolites, we found a class of acyl-CoAs that undergoes intramolecular catalysis to form reactive intermediates which non-enzymatically modify proteins. Based on this mechanism, we predicted, validated, and characterized the protein modification: 3-hydroxy-3-methylglutaryl(HMG)-lysine. In a model of altered HMG-CoA metabolism, we found evidence of two additional protein modifications: 3-methylglutaconyl(MGc)-lysine and 3-methylglutaryl(MG)-lysine. Using quantitative proteomics, we compared the ‘acylomes’ of two reactive acyl-CoA species, namely HMG-CoA and glutaryl-CoA, which are generated in different pathways. We found proteins that are uniquely modified by each reactive metabolite, as well as common proteins and pathways. We identified the tricarboxylic acid cycle as a pathway commonly regulated by acylation, and validated malate dehydrogenase as a key target. These data identify a fundamental relationship between reactive acyl-CoA species and proteins, and define a new regulatory paradigm in metabolism.
2017-04-11 | PXD005895 | Pride
Project description:5 day RNAi treatment to knockdown Enigma, CG9006, a Drosophila mitochondrial protein with homology to acyl-CoA dehydrogenases. Experiment Overall Design: Kc-167 cells, 5 day treatment with Enigma-specific RNAi or beta-lactamase control RNAi. Specifics:1.6X10^6 cells in 0.5mL of serum-free Sang's M3 media incubated for 1 hour with 20ug of dsRNA, subsequently equal volume of M3 media containing 10% serum was added. Cells harvested after 5 days. RNAi efficiency measured by immunoblot for Enigma.
2007-07-31 | E-GEOD-3566 | biostudies-arrayexpress
Project description:Long chain acyl-CoA synthetases (ACSL) and fatty acid transport proteins (FATP) activate fatty acids to acyl-CoAs in the initial step of fatty acid metabolism. Numerous isoforms of ACSL and FATP exist with different tissue distribution patterns, intracellular locations, and substrate preferences, suggesting that each isoform has distinct functions in channeling fatty acids into different metabolic pathways. Because fatty acids, acyl-CoAs, and downstream lipid metabolites regulate various transcription factors that control hepatic energy metabolism, we hypothesized that ACSL or FATP isoforms differentially regulate hepatic gene expression. Using small interference RNA (siRNA), we knocked down each liver-specific ACSL and FATP isoform in rat primary hepatocyte cultures and subsequently analyzed reporter gene activity of numerous transcription factors and performed quantitative mRNA analysis of their target genes. Compared with control cells, which were transfected with control siRNA, knockdown of acyl-CoA synthetase 3 (ACSL3) significantly decreased reporter gene activity of several lipogenic transcription factors such as peroxisome proliferator activation receptor-gamma, carbohydrate-responsive element-binding protein, sterol regulatory element-binding protein-1c, and liver X receptor-alpha and the expression of their target genes. These findings were further supported by metabolic labeling studies that showed [1-(14)C]acetate incorporation into lipid extracts was decreased in cells treated with ACSL3 siRNAs and that ACSL3 expression is up-regulated in ob/ob mice and mice fed a high sucrose diet. ACSL3 knockdown decreased total acyl-CoA synthetase activity without substantially altering the expression of other ACSL isoforms. In summary, these results identify a novel role for ACSL3 in mediating transcriptional control of hepatic lipogenesis.
| S-EPMC2781602 | biostudies-literature
Project description:Acyl-CoAs are essential for life. These metabolites serve as fundamental cellular building blocks in the biosynthesis of lipids, intermediates in energy production via the TCA cycle, and essential precursors for reversible protein acetylation. Each of these roles are dependent on acyl-CoA/protein interactions, physical contacts that can regulate protein function via a variety of mechanisms. We utilized systems-level analyses to characterize novel protein networks that interact with metabolic acyl-CoAs, and evaluate the potential of these interactions to facilitate enzyme activity or non-enzymatic acylation. Our studies provide a roadmap for integrating chemoproteomic data with systems biology analysis, and establish a novel resource for understanding the diverse signaling roles of acyl-CoAs in biology and disease.
2019-11-21 | PXD013157 | Pride
Project description:Acetyl-CoA synthetase (Acs) generates acetyl-Coenzyme A (Ac-CoA) but its excessive activity can deplete ATP and lead to growth arrest. To prevent this, Acs is tightly regulated through Ac-CoA-dependent feedback inhibition executed by Ac-CoA-dependent acetyltransferases such as AcuA in Bacillus subtilis. AcuA acetylates the catalytic lysine of AcsA turning the synthetase inactive. Here we report an Ac-CoA independent inhibition mechanism of AcsA, which relies on a complex between AcsA and AcuA. Our structural analysis reveals that AcuA and AcsA form a tightly intertwined complex – the C-terminal domain binds to acetyltransferase domain of AcuA, while the C-terminus of AcuA occupies the CoA-binding site in the N-terminal domain of AcsA. Our structure-guided biochemical analysis reveals that AcuA inhibits AcsA by an Ac-CoA-independent inhibition via the AcsA-AcuA complex, in addition to the well-known Ac-CoA-dependent inhibition via acetylation of the catalytic lysine 549 in AcsA disrupting the complex. These findings elucidate how AcuA specifically binds to its target and inhibits activity through an unprecedented Ac-CoA-independent mechanism when Ac-CoA levels are low. Our study suggests that the two mechanistically distinct inhibitory mechanisms accomplished by AcuA adjust AcsA activity to the cellular concentrations of the different substrates of the reaction, illustrating the complexity underlying the regulatory framework of acetyl-CoA synthesis from acetate.
2025-02-28 | PXD058390 | Pride