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      New dawn for cancer cell death: Emerging role of lipid metabolism

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          Abstract

          Background

          Resistance to cell death, a protective mechanism for removing damaged cells, is a “Hallmark of Cancer” that is essential for cancer progression. Increasing attention to cancer lipid metabolism has revealed a number of pathways that induce cancer cell death.

          Scope of review

          We summarize emerging concepts regarding lipid metabolic reprogramming in cancer that is mainly involved in lipid uptake and trafficking, de novo synthesis and esterification, fatty acid synthesis and oxidation, lipogenesis, and lipolysis. During carcinogenesis and progression, continuous metabolic adaptations are co-opted by cancer cells, to maximize their fitness to the ever-changing environmental. Lipid metabolism and the epigenetic modifying enzymes interact in a bidirectional manner which involves regulating cancer cell death. Moreover, lipids in the tumor microenvironment play unique roles beyond metabolic requirements that promote cancer progression. Finally, we posit potential therapeutic strategies targeting lipid metabolism to improve treatment efficacy and survival of cancer patient.

          Major conclusions

          The profound comprehension of past findings, current trends, and future research directions on resistance to cancer cell death will facilitate the development of novel therapeutic strategies targeting the lipid metabolism.

          Highlights

          • Lipid metabolic reprogramming is crucial for various aspects of cancer cell death.

          • Cancer cell growth depends on lipid metabolic plasticity and sustained metabolic adaptations.

          • Lipid metabolism and the epigenome interact in a bidirectional manner, which regulate cancer cell death.

          • The therapeutic strategies targeting lipid metabolism can improve treatment efficacy and survival of cancer patients.

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          Most cited references178

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          Hallmarks of Cancer: New Dimensions

          The hallmarks of cancer conceptualization is a heuristic tool for distilling the vast complexity of cancer phenotypes and genotypes into a provisional set of underlying principles. As knowledge of cancer mechanisms has progressed, other facets of the disease have emerged as potential refinements. Herein, the prospect is raised that phenotypic plasticity and disrupted differentiation is a discrete hallmark capability, and that nonmutational epigenetic reprogramming and polymorphic microbiomes both constitute distinctive enabling characteristics that facilitate the acquisition of hallmark capabilities. Additionally, senescent cells, of varying origins, may be added to the roster of functionally important cell types in the tumor microenvironment. SIGNIFICANCE: Cancer is daunting in the breadth and scope of its diversity, spanning genetics, cell and tissue biology, pathology, and response to therapy. Ever more powerful experimental and computational tools and technologies are providing an avalanche of "big data" about the myriad manifestations of the diseases that cancer encompasses. The integrative concept embodied in the hallmarks of cancer is helping to distill this complexity into an increasingly logical science, and the provisional new dimensions presented in this perspective may add value to that endeavor, to more fully understand mechanisms of cancer development and malignant progression, and apply that knowledge to cancer medicine.
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            ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.

            Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4-Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.
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              Molecular mechanisms of long noncoding RNAs.

              Long noncoding RNAs (lncRNAs) are an important class of pervasive genes involved in a variety of biological functions. Here we discuss the emerging archetypes of molecular functions that lncRNAs execute-as signals, decoys, guides, and scaffolds. For each archetype, examples from several disparate biological contexts illustrate the commonality of the molecular mechanisms, and these mechanistic views provide useful explanations and predictions of biological outcomes. These archetypes of lncRNA function may be a useful framework to consider how lncRNAs acquire properties as biological signal transducers and hint at their possible origins in evolution. As new lncRNAs are being discovered at a rapid pace, the molecular mechanisms of lncRNAs are likely to be enriched and diversified. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Mol Metab
                Mol Metab
                Molecular Metabolism
                Elsevier
                2212-8778
                15 June 2022
                September 2022
                15 June 2022
                : 63
                : 101529
                Affiliations
                [1 ]Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, PR China
                [2 ]TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, PR China
                [3 ]The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, 410021, PR China
                [4 ]Institutional Key Laboratory of Vascular Biology and Translational Medicine in Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, PR China
                [5 ]Hunan Province Engineering Research Center of Bioactive Substance Discovery of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, PR China
                Author notes
                []Corresponding author. lqin@ 123456hnucm.edu.cn
                [∗∗ ]Corresponding author. daiaiguo2003@ 123456163.com
                [∗∗∗ ]Corresponding author. wangwei402@ 123456hotmail.com
                Article
                S2212-8778(22)00098-9 101529
                10.1016/j.molmet.2022.101529
                9237930
                35714911
                a0f1232a-4ebb-464e-a573-f282a6be4126
                © 2022 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 15 May 2022
                : 30 May 2022
                : 11 June 2022
                Categories
                Review

                lipid metabolism,cancer,cell death,therapeutic strategy
                lipid metabolism, cancer, cell death, therapeutic strategy

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