Role of acyl-CoA synthetase ACSL4 in arachidonic acid metabolism

Kuwata, Hiroshi; Hara, Shuntaro

doi:10.1016/j.prostaglandins.2019.106363

Cited by 121 publications

(109 citation statements)

References 60 publications

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“…191 An additional pathway for AA metabolism is its conversion into arachidonyl-CoA following the ligation of acetyl-CoA catalysed by the acyl-CoA synthetase ACSL4. 192 Arachidonyl-CoA can be subsequently esterified to form TAGs and incorporated into phospholipids, or utilised as a substrate by COX2 to enhance eicosanoid biosynthesis. 193 ACSL4 is also implicated in the localised release of AA in the mitochondria, and this requires the transport of arachidonyl-CoA to the inner mitochondrial membrane via the translocator protein (TSPO) and hydrolysis by acyl-CoA thioesterase 2 (ACOT2).…”

Section: Fatty Acids Support Tumorigenesis and Cancer Progressionmentioning

confidence: 99%

“…193 ACSL4 is also implicated in the localised release of AA in the mitochondria, and this requires the transport of arachidonyl-CoA to the inner mitochondrial membrane via the translocator protein (TSPO) and hydrolysis by acyl-CoA thioesterase 2 (ACOT2). 192 Importantly, several studies have implicated ACSL4 in tumorigenesis, with advanced-stage breast, colorectal, hepatocellular and prostate carcinomas displaying increased expression at both the mRNA and protein levels. 192 The oncogenic effects of elevated ACSL4 are twofold.…”

Section: Fatty Acids Support Tumorigenesis and Cancer Progressionmentioning

confidence: 99%

“…192 Importantly, several studies have implicated ACSL4 in tumorigenesis, with advanced-stage breast, colorectal, hepatocellular and prostate carcinomas displaying increased expression at both the mRNA and protein levels. 192 The oncogenic effects of elevated ACSL4 are twofold. Firstly, mitochondrial AA that accumulates as a consequence of ACSL4 activity is predominantly directed towards the biosynthesis of leukotrienes including 5-, 12-and 15-hydroxyeicosatetraenoic acid (HETE).…”

Section: Fatty Acids Support Tumorigenesis and Cancer Progressionmentioning

confidence: 99%

“…195 ACSL4 limits the cytotoxicity associated with elevated cellular pools of unesterified AA by producing arachidonyl-CoA, thereby increasing the apoptotic threshold and survival of castration-resistant prostate cancer (CRPC) cells. 192 It is important to note, however, that the localised accumulation of arachidonyl-CoA and AA in the mitochondria can also contribute to membrane depolarisation and electron transport chain uncoupling, leading to increased ROS production. 196 If left unchecked, the elevation in ROS levels can increase lipid peroxidation and cell death induced by ferroptosis.…”

Section: Fatty Acids Support Tumorigenesis and Cancer Progressionmentioning

confidence: 99%

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Reprogramming of fatty acid metabolism in cancer

2019

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A common feature of cancer cells is their ability to rewire their metabolism to sustain the production of ATP and macromolecules needed for cell growth, division and survival. In particular, the importance of altered fatty acid metabolism in cancer has received renewed interest as, aside their principal role as structural components of the membrane matrix, they are important secondary messengers, and can also serve as fuel sources for energy production. In this review, we will examine the mechanisms through which cancer cells rewire their fatty acid metabolism with a focus on four main areas of research. (1) The role of de novo synthesis and exogenous uptake in the cellular pool of fatty acids. (2) The mechanisms through which molecular heterogeneity and oncogenic signal transduction pathways, such as PI3K-AKT-mTOR signalling, regulate fatty acid metabolism. (3) The role of fatty acids as essential mediators of cancer progression and metastasis, through remodelling of the tumour microenvironment. (4) Therapeutic strategies and considerations for successfully targeting fatty acid metabolism in cancer. Further research focusing on the complex interplay between oncogenic signalling and dysregulated fatty acid metabolism holds great promise to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.

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Section: Fatty Acids Support Tumorigenesis and Cancer Progressionmentioning

confidence: 99%

Section: Fatty Acids Support Tumorigenesis and Cancer Progressionmentioning

confidence: 99%

Section: Fatty Acids Support Tumorigenesis and Cancer Progressionmentioning

confidence: 99%

Section: Fatty Acids Support Tumorigenesis and Cancer Progressionmentioning

confidence: 99%

See 2 more Smart Citations

Reprogramming of fatty acid metabolism in cancer

2019

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“…ACSLs activate fatty acids through ATP-dependent Coenzyme A thioesterification to generate fatty acyl-CoAs that can enter a number of intracellular lipid metabolic pathways [14][15][16][17]. ACSL3 and ACSL4 are structurally homologous enzymes; however, they differ in their fatty acid substrate specificities, expression patterns in various tissues and subcellular localisations [8,14,[18][19][20]. ACSL3 preferentially and equally activates palmitic and arachidonic fatty acids, whereas ACSL4 preferentially activates arachidonic acid [21].…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical staining reveals differential expression of ACSL3 and ACSL4 in hepatocellular carcinoma and hepatic gastrointestinal metastases

et al. 2020

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Long-chain fatty acyl CoA synthetases (ACSLs) activate fatty acids by CoA addition thus facilitating their intracellular metabolism. Dysregulated ACSL expression features in several cancers and can affect processes such as ferroptosis, fatty acid β-oxidation, prostaglandin biosynthesis, steroidogenesis and phospholipid acyl chain remodelling. Here we investigate long chain acyl-CoA synthetase 3 (ACSL3) and long chain acyl-CoA synthetase 4 (ACSL4) expression in liver malignancies. The expression and subcellular localisations of the ACSL3 and ACSL4 isoforms in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA) and hepatic metastases were assessed by immunohistochemical analyses of multiple tumour tissue arrays and by subcellular fractionation of cultured HepG2 cells. The expression of both enzymes was increased in HCC compared with normal liver. Expression of ACSL3 was similar in HCC and hepatic metastases but lower in healthy tissue. Increased ACSL3 expression distinguished HCC from CCA with a sensitivity of 87.2% and a specificity of 75%. ACSL4 expression was significantly greater in HCC than in all other tumours and distinguished HCC from normal liver tissue with a sensitivity of 93.8% and specificity of 93.6%. Combined ACSL3 and ACSL4 staining scores distinguished HCC from hepatic metastases with 80.1% sensitivity and 77.1% specificity. These enzymes had partially overlapping intracellular distributions, ACSL4 localised to the plasma membrane and both isoforms associated with lipid droplets and the endoplasmic reticulum (ER). In conclusion, analysis of ACSL3 and ACSL4 expression can distinguish different classes of hepatic tumours.

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The role of ferroptosis as a regulator of oxidative stress in the pathogenesis of ischemic stroke

Delgado‐Martín,

Martínez‐Ruiz

2024

FEBS Letters

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Ferroptosis is a unique form of cell death that was first described in 2012 and plays a significant role in various diseases, including neurodegenerative conditions. It depends on a dysregulation of cellular iron metabolism, which increases free, redox‐active, iron that can trigger Fenton reactions, generating hydroxyl radicals that damage cells through oxidative stress and lipid peroxidation. Lipid peroxides, resulting mainly from unsaturated fatty acids, damage cells by disrupting membrane integrity and propagating cell death signals. Moreover, lipid peroxide degradation products can further affect cellular components such as DNA, proteins, and amines. In ischemic stroke, where blood flow to the brain is restricted, there is increased iron absorption, oxidative stress, and compromised blood–brain barrier integrity. Imbalances in iron‐transport and ‐storage proteins increase lipid oxidation and contribute to neuronal damage, thus pointing to the possibility of brain cells, especially neurons, dying from ferroptosis. Here, we review the evidence showing a role of ferroptosis in ischemic stroke, both in recent studies directly assessing this type of cell death, as well as in previous studies showing evidence that can now be revisited with our new knowledge on ferroptosis mechanisms. We also review the efforts made to target ferroptosis in ischemic stroke as a possible treatment to mitigate cellular damage and death.

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Role of acyl-CoA synthetase ACSL4 in arachidonic acid metabolism

Cited by 121 publications

References 60 publications

Reprogramming of fatty acid metabolism in cancer

Reprogramming of fatty acid metabolism in cancer

Immunohistochemical staining reveals differential expression of ACSL3 and ACSL4 in hepatocellular carcinoma and hepatic gastrointestinal metastases

The role of ferroptosis as a regulator of oxidative stress in the pathogenesis of ischemic stroke

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