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      Lipid metabolic reprogramming in cancer cells

      review-article
      1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , *
      Oncogenesis
      Nature Publishing Group

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          Abstract

          Many human diseases, including metabolic, immune and central nervous system disorders, as well as cancer, are the consequence of an alteration in lipid metabolic enzymes and their pathways. This illustrates the fundamental role played by lipids in maintaining membrane homeostasis and normal function in healthy cells. We reviewed the major lipid dysfunctions occurring during tumor development, as determined using systems biology approaches. In it, we provide detailed insight into the essential roles exerted by specific lipids in mediating intracellular oncogenic signaling, endoplasmic reticulum stress and bidirectional crosstalk between cells of the tumor microenvironment and cancer cells. Finally, we summarize the advances in ongoing research aimed at exploiting the dependency of cancer cells on lipids to abolish tumor progression.

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          Most cited references98

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          On the origin of cancer cells.

          O WARBURG (1956)
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            Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism

            Tumor maintenance relies on continued activity of driver oncogenes, although their rate-limiting role is highly context dependent. Oncogenic Kras mutation is the signature event in pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible Kras(G12D)-driven PDAC mouse model establishes that advanced PDAC remains strictly dependent on Kras(G12D) expression. Transcriptome and metabolomic analyses indicate that Kras(G12D) serves a vital role in controlling tumor metabolism through stimulation of glucose uptake and channeling of glucose intermediates into the hexosamine biosynthesis and pentose phosphate pathways (PPP). These studies also reveal that oncogenic Kras promotes ribose biogenesis. Unlike canonical models, we demonstrate that Kras(G12D) drives glycolysis intermediates into the nonoxidative PPP, thereby decoupling ribose biogenesis from NADP/NADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in PDAC. Copyright © 2012 Elsevier Inc. All rights reserved.
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              De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation.

              Activation of de novo lipogenesis in cancer cells is increasingly recognized as a hallmark of aggressive cancers and has been implicated in the production of membranes for rapid cell proliferation. In the current report, we provide evidence that this activation has a more profound role. Using a mass spectrometry-based phospholipid analysis approach, we show that clinical tumor tissues that display the lipogenic phenotype show an increase in the degree of lipid saturation compared with nonlipogenic tumors. Reversal of the lipogenic switch in cancer cells by treatment with the lipogenesis inhibitor soraphen A or by targeting lipogenic enzymes with small interfering RNA leads to a marked decrease in saturated and mono-unsaturated phospholipid species and increases the relative degree of polyunsaturation. Because polyunsaturated acyl chains are more susceptible to peroxidation, inhibition of lipogenesis increases the levels of peroxidation end products and renders cells more susceptible to oxidative stress-induced cell death. As saturated lipids pack more densely, modulation of lipogenesis also alters lateral and transversal membrane dynamics as revealed by diffusion of membrane-targeted green fluorescent protein and by the uptake and response to doxorubicin. These data show that shifting lipid acquisition from lipid uptake toward de novo lipogenesis dramatically changes membrane properties and protects cells from both endogenous and exogenous insults. These findings provide important new insights into the role of de novo lipogenesis in cancer cells, and they provide a rationale for the use of lipogenesis inhibitors as antineoplastic agents and as chemotherapeutic sensitizers. ©2010 AACR.
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                Author and article information

                Journal
                Oncogenesis
                Oncogenesis
                Oncogenesis
                Nature Publishing Group
                2157-9024
                January 2016
                25 January 2016
                1 January 2016
                : 5
                : 1
                : e189
                Affiliations
                [1 ]INSERM, U1068, Centre de Recherche en Cancérologie de Marseille , Marseille, France
                [2 ]Institut Paoli-Calmettes , Marseille, France
                [3 ]CNRS, UMR7258, Marseille, France
                [4 ]Université Aix-Marseille , Marseille, France
                Author notes
                [* ]INSERM, U1068, CRCM , 163, Avenue de Luminy, Parc Scientifique de Luminy, Case 915, Marseille 13009, France. E-mail: fabienne.marchai@ 123456inserm.fr
                Article
                oncsis201549
                10.1038/oncsis.2015.49
                4728678
                26807644
                37ea0aa9-e35d-4ea8-93c7-5fa0d113d51c
                Copyright © 2016 Macmillan Publishers Limited

                Oncogenesis is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 01 October 2015
                : 10 December 2015
                : 16 December 2015
                Categories
                Review

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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