An update on the therapeutic implications of long-chain acyl-coenzyme A synthetases in nervous system diseases

Wu, Zhimin; Sun, Jun; Li, Zhi; Qiao, Jie; Chen, Chuan; Ling, Cong; Wang, Hui

doi:10.3389/fnins.2022.1030512

Cited by 4 publications

(3 citation statements)

References 116 publications

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“… 50 The extent of intracellular lipid peroxidation and associated ferroptosis is dependent upon the abundance and localization of polyunsaturated FA. 51 ACSL1, 3 and 5 were reported to be associated with ferroptosis‐associated disease, 52 and ACSL5 was also associated with apoptosis. 53 …”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidylcholine inhibits lung cancer cell proliferation by regulating fatty acid metabolism enzyme long‐chain acyl‐coenzyme A synthase 5

Zhang

Liu

et al. 2023

Clinical & Translational Med

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Lung cancer is a widespread malignancy with a high death rate and disorder of lipid metabolism. Lysophosphatidylcholine (lysoPC) has anti-tumour effects, although the underlying mechanism is not entirely known. The purpose of this study aims at defining changes in lysoPC in lung cancer patients, the effects of lysoPC on lung cancer cells and molecular mechanisms. Lung cancer cell sensitivity to lysoPC was evaluated and decisive roles of long-chain acyl-coenzyme A synthase 5 (ACSL5) in lysoPC regulation were defined by comprehensively evaluating transcriptomic changes of ACSL5-downregulated epithelia. ACSL5 over-expressed in ciliated, club and Goblet cells in lung cancer patients, different from other lung diseases. LysoPC inhibited lung cancer cell proliferation, by inducing mitochondrial dysfunction, altering lipid metabolisms, increasing fatty acid oxidation and reprograming ACSL5/phosphoinositide 3-kinase/extracellular signal-regulated kinase-regulated triacylglycerol-lysoPC balance. Thus, this study provides a general new basis for the discovery of reprogramming metabolisms and metabolites as a new strategy of lung cancer precision medicine.

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Section: Discussionmentioning

confidence: 99%

Lysophosphatidylcholine inhibits lung cancer cell proliferation by regulating fatty acid metabolism enzyme long‐chain acyl‐coenzyme A synthase 5

Zhang

Liu

et al. 2023

Clinical & Translational Med

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“…5D). ACSLs (ACSL1, 3, 4, 5, and 6) are a family of CoA synthetases that activate long-chain FAs into acyl-CoA for the synthesis of cellular lipids and are thought to affect cell proliferation, including in nervous system diseases [46]. It is currently known that actively proliferating cancer cells often activate de novo fatty acid synthesis to provide essential structural components, e.g., structural lipids, for their growth [47].…”

Section: Rest-null Gbm Cells Can Rescue Their Growth Through Lipid Me...mentioning

confidence: 99%

Targeting of REST with rationally-designed small molecule compounds exhibits synergetic therapeutic potential in human glioblastoma cells

Panina,

Schweer,

Zhang

et al. 2024

BMC Biol

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Background Glioblastoma (GBM) is an aggressive brain cancer associated with poor prognosis, intrinsic heterogeneity, plasticity, and therapy resistance. In some GBMs, cell proliferation is fueled by a transcriptional regulator, repressor element-1 silencing transcription factor (REST). Results Using CRISPR/Cas9, we identified GBM cell lines dependent on REST activity. We developed new small molecule inhibitory compounds targeting small C-terminal domain phosphatase 1 (SCP1) to reduce REST protein level and transcriptional activity in glioblastoma cells. Top leads of the series like GR-28 exhibit potent cytotoxicity, reduce REST protein level, and suppress its transcriptional activity. Upon the loss of REST protein, GBM cells can potentially compensate by rewiring fatty acid metabolism, enabling continued proliferation. Combining REST inhibition with the blockade of this compensatory adaptation using long-chain acyl-CoA synthetase inhibitor Triacsin C demonstrated substantial synergetic potential without inducing hepatotoxicity. Conclusions Our results highlight the efficacy and selectivity of targeting REST alone or in combination as a therapeutic strategy to combat high-REST GBM.

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“…The ACSLs isoforms mainly involves both anabolic (lipogenesis) and catabolic pathways (fatty acid oxidation and lipolysis), among which ACSL1 and ACSL4 are the most extensively studied in the lipid metabolic reprogramming of cancer. [146,147] The lipid-metabolic related lncR-NAs and circRNAs in cancers have also been discovered to play roles in the regulation of ACSL1 and ACSL4 expressions (Figure 5 and Table 3). For instance, lncRNA HULC was identified to modulate the lipid metabolic programming of HCC.…”

Section: The Lncrnas-circrnas In Regulating Lipid Esterification and ...mentioning

confidence: 99%

LncRNAs‐circRNAs as Rising Epigenetic Binary Superstars in Regulating Lipid Metabolic Reprogramming of Cancers

Liu,

Jiao,

Zhao

et al. 2023

Advanced Science

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As one of novel hallmarks of cancer, lipid metabolic reprogramming has recently been becoming fascinating and widely studied. Lipid metabolic reprogramming in cancer is shown to support carcinogenesis, progression, distal metastasis, and chemotherapy resistance by generating ATP, biosynthesizing macromolecules, and maintaining appropriate redox status. Notably, increasing evidence confirms that lipid metabolic reprogramming is under the control of dysregulated non‐coding RNAs in cancer, especially lncRNAs and circRNAs. This review highlights the present research findings on the aberrantly expressed lncRNAs and circRNAs involved in the lipid metabolic reprogramming of cancer. Emphasis is placed on their regulatory targets in lipid metabolic reprogramming and associated mechanisms, including the clinical relevance in cancer through lipid metabolism modulation. Such insights will be pivotal in identifying new theranostic targets and treatment strategies for cancer patients afflicted with lipid metabolic reprogramming.

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An update on the therapeutic implications of long-chain acyl-coenzyme A synthetases in nervous system diseases

Cited by 4 publications

References 116 publications

Lysophosphatidylcholine inhibits lung cancer cell proliferation by regulating fatty acid metabolism enzyme long‐chain acyl‐coenzyme A synthase 5

Lysophosphatidylcholine inhibits lung cancer cell proliferation by regulating fatty acid metabolism enzyme long‐chain acyl‐coenzyme A synthase 5

Targeting of REST with rationally-designed small molecule compounds exhibits synergetic therapeutic potential in human glioblastoma cells

LncRNAs‐circRNAs as Rising Epigenetic Binary Superstars in Regulating Lipid Metabolic Reprogramming of Cancers

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