ACSL family: The regulatory mechanisms and therapeutic implications in cancer

Quan, Jing; Bode, Ann M.; Luo, Xiangjian

doi:10.1016/j.ejphar.2021.174397

Cited by 148 publications

(115 citation statements)

References 92 publications

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“…Through screening the transcription profile of lipid metabolism-related genes, we found that ACSL3 is among the most significantly up-regulated genes during the process of EMT induced by TGFβ1. ACSL3 is placed at a critical intersection of lipid anabolic and catabolic pathways, which is responsible for activating long-chain FAs to provide substrates for both lipid synthesis and β-oxidation 7 , 36 . ACSL3 is closely associated with tumorigenesis and malignant progression in a variety of cancers 37 - 40 .…”

Section: Discussionmentioning

confidence: 99%

Acyl-CoA synthetase long-chain 3-mediated fatty acid oxidation is required for TGFβ1-induced epithelial-mesenchymal transition and metastasis of colorectal carcinoma

Quan¹,

Cheng²,

Tan³

et al. 2022

Int. J. Biol. Sci.

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Cancer cells frequently undergo metabolic reprogramming to support tumorigenicity and malignancy, which is recognized as a hallmark of cancer. In addition to glycolysis and glutaminolysis, alterations in fatty acid (FA) metabolism have received increasing concerns in the past few years. Recently, accumulating evidence has shown that fatty acid β-oxidation (FAO) is abnormally activated in various tumors, which is associated with the machinery of proliferation, stemness, metastasis, and radiochemotherapeutic resistance of cancer cells. Acyl-CoA synthetases 3 (ACSL3) belongs to a family of enzymes responsible for converting free long-chain FAs into fatty acyl-CoA esters, which act as substrates both for lipid synthesis and FAO. Here, we demonstrate that transforming growth factor beta 1 (TGFβ1) induces the up-regulation of ACSL3 through sterol regulatory element-binding protein 1 (SREBP1) signaling to promote energy metabolic reprogramming in colorectal carcinoma (CRC) cells. ACSL3 mediates the epithelial mesenchymal transition (EMT) and metastasis of CRC cells by activation of FAO pathway to produce ATP and reduced nicotinamide adenine dinucleotide phosphate (NADPH), which sustain redox homeostasis and fuel cancer cells for invasion and distal metastasis. Thus, targeting ACSL3 and FAO metabolic pathways might be exploited for therapeutic gain for CRC and other FAs- addicted cancers.

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Section: Discussionmentioning

confidence: 99%

Acyl-CoA synthetase long-chain 3-mediated fatty acid oxidation is required for TGFβ1-induced epithelial-mesenchymal transition and metastasis of colorectal carcinoma

Quan¹,

Cheng²,

Tan³

et al. 2022

Int. J. Biol. Sci.

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“…Lin ( 43 ) demonstrated that PTGS2 mediated cisplatin-induced BCL2 expression and subsequent apoptosis resistance through a PGE2/EP4/MAPK (ERK1/2, P38)-dependent mechanism. The ACSL family mainly catalyzes fatty acids with 12–20 carbon chains ( 44 ). Evidence has shown that ACSLs are enzymes crucial for the body’s response to fatty acid metabolism ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology Study and Experimental Validation of Yiqi Huayu Decoction Inducing Ferroptosis in Gastric Cancer

Song

Fang

et al. 2022

Front. Oncol.

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ObjectiveThis study aimed to identify the mechanism of Yiqi Huayu Decoction (YQHY) induced ferroptosis in gastric cancer (GC) by using network pharmacology and experimental validation.MethodsThe targets of YQHY, ferroptosis-related targets, and targets related to GC were derived from databases. Following the protein–protein interaction (PPI) network, the hub targets for YQHY induced ferroptosis in GC were identified. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were used to analyze the hub targets from a macro perspective. We verified the hub targets by molecular docking, GEPIA, HPA, and the cBioPortal database. Finally, we performed cell viability assays, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, lipid peroxidation, and GSH assays to explore the mechanism of YQHY induced ferroptosis in GC.ResultsWe identified the main active compounds and hub targets: Quercetin, DIBP, DBP, Mipax, Phaseol and TP53, ATM, SMAD4, PTGS2, and ACSL4. KEGG enrichment analyses indicated that the JAK2-STAT3 signaling pathway may be a significant pathway. Molecular docking results showed that the main active compounds had a good binding activity with the hub targets. The experimental results proved that YQHY could induce ferroptosis in AGS by increasing the MDA content and reducing the GSH content. qRT–PCR and Western blot results showed that YQHY can induce ferroptosis in GC by affecting the JAK2-STAT3 pathway and the expression of ACSL4.ConclusionsThis study indicated that YQHY can induce ferroptosis in GC by affecting the JAK2–STAT3 pathway and the expression of ACSL4, and induction of ferroptosis may be one of the possible mechanisms of YQHY’s anti-recurrence and metastasis of GC.

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“…Hence, further studies on the effect of the TP53 mutation site on ferroptosis in SKCM patients are required. ACSL5, belonging to the acyl-CoA synthetase long-chain (ACSL) family, is a nuclear-coded pro-apoptotic gene that participates in cancer suppressors; however, it shows a prooncogenic role in gastric cancer (Quan et al, 2021). TF encodes a glycoprotein that transports iron and removes allergens from serum.…”

Section: Discussionmentioning

confidence: 99%

“…Genecluster F had the most satisfactory overall survival rate, in which the ACSL family, SLC family, NCOA4, TF, and HMOX1 were upregulated, while GPX4 and TP53 were downregulated. In the review of ACSLs by Quan et al (2021), the ACSL family contains five members, ACSL1 and ACSL3-6 in mammals, which regulate lipid metabolism and act as the key factors of ferroptosis. ACSL4 maintains a flexible role as a suppressor or an oncogene in different cancers, ACSL5 physiologically acts as a tumor suppressor in cancers, and ASCL6 is downregulated in diverse kinds of cancers, in addition to colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

A Novel Ferroptosis-Related lncRNA Prognostic Model and Immune Infiltration Features in Skin Cutaneous Melanoma

Sun

Zhang

2022

Front. Cell Dev. Biol.

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Background: Skin cutaneous melanoma (SKCM) is an aggressive malignant skin tumor. Ferroptosis is an iron-dependent cell death that may mobilize tumor-infiltrating immunity against cancer. The potential mechanism of long non-coding RNAs (lncRNAs) in ferroptosis in SKCM is not clear. In this study, the prognostic and treatment value of ferroptosis-related lncRNAs was explored in SKCM, and a prognostic model was established.Methods: We first explored the mutation state of ferroptosis-related genes in SKCM samples from The Cancer Genome Atlas database. Then, we utilized consensus clustering analysis to divide the samples into three clusters based on gene expression and evaluated their immune infiltration using gene-set enrichment analysis (GSEA) ESTIMATE and single-sample gene-set enrichment analysis (ssGSEA) algorithms. In addition, we applied univariate Cox analysis to screen prognostic lncRNAs and then validated their prognostic value by Kaplan–Meier (K-M) and transcripts per kilobase million (TPM) value analyses. Finally, we constructed an 18-ferroptosis-related lncRNA prognostic model by multivariate Cox analysis, and SKCM patients were allocated into different risk groups based on the median risk score. The prognostic value of the model was evaluated by K-M and time-dependent receiver operating characteristic (ROC) analyses. Additionally, the immunophenoscore (IPS) in different risk groups was detected.Results: The top three mutated ferroptosis genes were TP53, ACSL5, and TF. The SKCM patients in the cluster C had the highest ferroptosis-related gene expression with the richest immune infiltration. Based on the 18 prognosis-related lncRNAs, we constructed a prognostic model of SKCM patients. Patients at low risk had a better prognosis and higher IPS.Conclusion: Our findings revealed that ferroptosis-related lncRNAs were expected to become potential biomarkers and indicators of prognosis and immunotherapy treatment targets of SKCM.

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ACSL family: The regulatory mechanisms and therapeutic implications in cancer

Cited by 148 publications

References 92 publications

Acyl-CoA synthetase long-chain 3-mediated fatty acid oxidation is required for TGFβ1-induced epithelial-mesenchymal transition and metastasis of colorectal carcinoma

Acyl-CoA synthetase long-chain 3-mediated fatty acid oxidation is required for TGFβ1-induced epithelial-mesenchymal transition and metastasis of colorectal carcinoma

Network Pharmacology Study and Experimental Validation of Yiqi Huayu Decoction Inducing Ferroptosis in Gastric Cancer

A Novel Ferroptosis-Related lncRNA Prognostic Model and Immune Infiltration Features in Skin Cutaneous Melanoma

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