Targeting Long Chain Acyl-CoA Synthetases for Cancer Therapy

Sebastiano, Matteo Rossi; Konstantinidou, Georgia

doi:10.3390/ijms20153624

Cited by 101 publications

(75 citation statements)

References 102 publications

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“…Acyl-CoA Synthetase Long Chain Family Member (ACSL) catalyzes the formation of fatty acyl-CoA from fatty acids and isoforms 1, 3, and 4 are more often overexpressed in cancer cells and specifically in colorectal (269), breast (270) and prostate cancers (271). Each isoform uses different substrates e.g., ACSL1 uses oleate and linoleate, ACSL3 uses myristate, palmitate, arachidonate and eicosapentaenoate and ACSL4 arachidonate (272). This activation of fatty acids by ACSL is a necessary step for the synthesis of cellular lipids as well as the β-oxidation.…”

Section: Lipid Metabolismmentioning

confidence: 99%

EMT Factors and Metabolic Pathways in Cancer

Georgakopoulos-Soares

et al. 2020

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The epithelial-mesenchymal transition (EMT) represents a biological program during which epithelial cells lose their cell identity and acquire a mesenchymal phenotype. EMT is normally observed during organismal development, wound healing and tissue fibrosis. However, this process can be hijacked by cancer cells and is often associated with resistance to apoptosis, acquisition of tissue invasiveness, cancer stem cell characteristics, and cancer treatment resistance. It is becoming evident that EMT is a complex, multifactorial spectrum, often involving episodic, transient or partial events. Multiple factors have been causally implicated in EMT including transcription factors (e.g., SNAIL, TWIST, ZEB), epigenetic modifications, microRNAs (e.g., miR-200 family) and more recently, long non-coding RNAs. However, the relevance of metabolic pathways in EMT is only recently being recognized. Importantly, alterations in key metabolic pathways affect cancer development and progression. In this review, we report the roles of key EMT factors and describe their interactions and interconnectedness. We introduce metabolic pathways that are involved in EMT, including glycolysis, the TCA cycle, lipid and amino acid metabolism, and characterize the relationship between EMT factors and cancer metabolism. Finally, we present therapeutic opportunities involving EMT, with particular focus on cancer metabolic pathways.

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Section: Lipid Metabolismmentioning

confidence: 99%

EMT Factors and Metabolic Pathways in Cancer

Georgakopoulos-Soares

et al. 2020

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“…Triacsin C has been administered to mice daily for up to two months without overt signs of significant toxicity and resulted in a decrease in atherosclerosis 53 . However, the pharmacokinetics and cell penetrance of Triacsin C are viewed as significant impediments to its clinical use 54 . Despite this, Triacsin C analogs have been developed 15 , and long chain fatty acyl CoA synthetases are of interest as potential therapeutics for cancer as well as for viruses 54 .…”

Section: Vps34mentioning

confidence: 99%

Inhibitors of VPS34 and lipid metabolism suppress SARS-CoV-2 replication

Silvas

Jureka

Nicolini

et al. 2020

Preprint

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Therapeutics targeting replication of SARS coronavirus 2 (SARS-CoV-2) are urgently needed. Coronaviruses rely on host membranes for entry, establishment of replication centers and egress. Compounds targeting cellular membrane biology and lipid biosynthetic pathways have previously shown promise as antivirals and are actively being pursued as treatments for other conditions. Here, we tested small molecule inhibitors that target membrane dynamics or lipid metabolism. Included were inhibitors of the PI3 kinase VPS34, which functions in autophagy, endocytosis and other processes; Orlistat, an inhibitor of lipases and fatty acid synthetase, is approved by the FDA as a treatment for obesity; and Triacsin C which inhibits long chain fatty acyl-CoA synthetases. VPS34 inhibitors, Orlistat and Triacsin C inhibited virus growth in Vero E6 cells and in the human airway epithelial cell line Calu-3, acting at a post-entry step in the virus replication cycle. Of these the VPS34 inhibitors exhibit the most potent activity.

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“…Therefore, ACSL1 acts as an important player in immunometabolism [92]. Thus, pharmacological inhibition of ACSL1 may provide promising therapeutic value in treating inflammatory-associated disorders such as cancer [93].…”

Section: Targeting Of Palmitate-induced Pathways As a Therapeutic Strmentioning

confidence: 99%

Shaping of Innate Immune Response by Fatty Acid Metabolite Palmitate

Tzeng

Chyuan

Chen

2019

Cells

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Innate immune cells monitor invading pathogens and pose the first-line inflammatory response to coordinate with adaptive immunity for infection removal. Innate immunity also plays pivotal roles in injury-induced tissue remodeling and the maintenance of tissue homeostasis in physiological and pathological conditions. Lipid metabolites are emerging as the key players in the regulation of innate immune responses, and recent work has highlighted the importance of the lipid metabolite palmitate as an essential component in this regulation. Palmitate modulates innate immunity not only by regulating the activation of pattern recognition receptors in local innate immune cells, but also via coordinating immunological activity in inflammatory tissues. Moreover, protein palmitoylation controls various cellular physiological processes. Herein, we review the updated evidence that palmitate catabolism contributes to innate immune cell-mediated inflammatory processes that result in immunometabolic disorders.Fatty acid β-oxidation is a major process that provides energy by degrading fatty acids. The enzymes responsible for fatty acid β-oxidation are mainly located in the mitochondria and peroxisomes. Each β-oxidation cycle can generate one acetyl-CoA molecule, which serves as the source for tricarboxylic acid cycle progression and yields more ATP per carbon than that from sugars by oxidative phosphorylation [7]. In contrast to the removal of two carbons from long-chain fatty acids in each β-oxidation round, fatty acid synthesis is catalyzed by joining two carbon units to the growing acyl chain via the cytosolic fatty acid synthase complex [8]. Palmitate is a 16-carbon saturated fatty acid produced via the fatty acid synthesis pathway in a fatty acid synthase-dependent manner, and acts as the major lipid mediator in inflammatory response regulation. Palmitic Acid-Regulated Innate Immune ResponsesCell uptake of palmitate is mainly mediated by the membrane fatty acid transporter CD36, also known as scavenger receptor B2 [9], although palmitate can also enter cells by other mechanisms, including direct membrane interactions, albumin-mediated transfer, and lipoprotein lipase-mediated uptake [10]. Accumulating evidence suggests a critical role by palmitic acid in modulating the activation of pattern recognition receptors in innate immune cells (Figure 1). Indeed, accumulating evidence reveals that although not through direct engagement of Toll-like receptors (TLRs), palmitate can modulate TLR downstream signaling in response to their ligand stimulation [11,12]. Palmitate is believed to be a TLR4 agonist that promotes macrophage activation and lipid metabolism-associated inflammation. Recently, however, it has been demonstrated that palmitate-induced inflammatory effects are not triggered by the direct binding of palmitate to TLR4, but through a combination of palmitate-mediated and TLR4-dependent priming, which alters cellular lipid metabolic pathways, gene expression, and membrane lipid composition, the prerequisite changes that are ...

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Targeting Long Chain Acyl-CoA Synthetases for Cancer Therapy

Cited by 101 publications

References 102 publications

EMT Factors and Metabolic Pathways in Cancer

EMT Factors and Metabolic Pathways in Cancer

Inhibitors of VPS34 and lipid metabolism suppress SARS-CoV-2 replication

Shaping of Innate Immune Response by Fatty Acid Metabolite Palmitate

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