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Inhibition of StearoylCoA Desaturase-1 Inactivates Acetyl-CoA Carboxylase and Impairs Proliferation in Cancer Cells: Role of AMPK

1 , 2 , 1 , *

PLoS ONE

Public Library of Science

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      Abstract

      Cancer cells activate the biosynthesis of saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) in order to sustain an increasing demand for phospholipids with appropriate acyl composition during cell replication. We have previously shown that a stable knockdown of stearoyl-CoA desaturase 1 (SCD1), the main Δ9-desaturase that converts SFA into MUFA, in cancer cells decreases the rate of lipogenesis, reduces proliferation and in vitro invasiveness, and dramatically impairs tumor formation and growth. Here we report that pharmacological inhibition of SCD1 with a novel small molecule in cancer cells promoted the activation of AMP-activated kinase (AMPK) and the subsequent reduction of acetylCoA carboxylase activity, with a concomitant inhibition of glucose-mediated lipogenesis. The pharmacological inhibition of AMPK further decreased proliferation of SCD1-depleted cells, whereas AMPK activation restored proliferation to control levels. Addition of supraphysiological concentrations of glucose or pyruvate, the end product of glycolysis, did not reverse the low proliferation rate of SCD1-ablated cancer cells. Our data suggest that cancer cells require active SCD1 to control the rate of glucose-mediated lipogenesis, and that when SCD1 activity is impaired cells downregulate SFA synthesis via AMPK-mediated inactivation of acetyl-CoA carboxylase, thus preventing the harmful effects of SFA accumulation.

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        The biology of cancer: metabolic reprogramming fuels cell growth and proliferation.

        Cell proliferation requires nutrients, energy, and biosynthetic activity to duplicate all macromolecular components during each passage through the cell cycle. It is therefore not surprising that metabolic activities in proliferating cells are fundamentally different from those in nonproliferating cells. This review examines the idea that several core fluxes, including aerobic glycolysis, de novo lipid biosynthesis, and glutamine-dependent anaplerosis, form a stereotyped platform supporting proliferation of diverse cell types. We also consider regulation of these fluxes by cellular mediators of signal transduction and gene expression, including the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR system, hypoxia-inducible factor 1 (HIF-1), and Myc, during physiologic cell proliferation and tumorigenesis.
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          Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis.

          There is a renewed interest in the ultimate role of fatty acid synthase (FASN)--a key lipogenic enzyme catalysing the terminal steps in the de novo biogenesis of fatty acids--in cancer pathogenesis. Tumour-associated FASN, by conferring growth and survival advantages rather than functioning as an anabolic energy-storage pathway, appears to necessarily accompany the natural history of most human cancers. A recent identification of cross-talk between FASN and well-established cancer-controlling networks begins to delineate the oncogenic nature of FASN-driven lipogenesis. FASN, a nearly-universal druggable target in many human carcinomas and their precursor lesions, offers new therapeutic opportunities for metabolically treating and preventing cancer.
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            Author and article information

            Affiliations
            [1 ]Department of Nutritional Sciences and Rutgers Center for Lipid Research, Rutgers, the State University of New Jersey, New Brunswick, New Jersey, United States of America
            [2 ]Biology, Gilead Sciences, Inc., Palo Alto, California, United States of America
            National Institutes of Health (NIH)/National Institute of Environmental Health Sciences (NIEHS), United States of America
            Author notes

            Conceived and designed the experiments: RAI. Performed the experiments: NS JWC RAI. Analyzed the data: NS JWC RAI. Contributed reagents/materials/analysis tools: JWC RAI. Wrote the paper: NS JWC RAI.

            Contributors
            Role: Editor
            Journal
            PLoS One
            plos
            plosone
            PLoS ONE
            Public Library of Science (San Francisco, USA )
            1932-6203
            2009
            27 August 2009
            : 4
            : 8
            2728543
            19710915
            09-PONE-RA-10130R1
            10.1371/journal.pone.0006812
            (Editor)
            Scaglia et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
            Counts
            Pages: 14
            Categories
            Research Article
            Nutrition
            Biochemistry/Biocatalysis
            Biochemistry/Cell Signaling and Trafficking Structures
            Biochemistry/Membrane Proteins and Energy Transduction
            Nutrition/Obesity
            Oncology/Breast Cancer
            Oncology/Lung Cancer

            Uncategorized

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