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De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy

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      Abstract

      Enhanced lipid biosynthesis is a characteristic feature of cancer. Deregulated lipogenesis plays an important role in tumour cell survival. These observations suggest that enzymes in the lipid synthesis pathway would be rational therapeutic targets for cancer. To this end, we review the enzymes in de novo fatty-acid synthesis and related pathways.

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      Most cited references 34

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      On the origin of cancer cells.

       O WARBURG (1956)
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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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          ATP citrate lyase inhibition can suppress tumor cell growth.

          Many tumors display a high rate of glucose utilization, as evidenced by 18-F-2-deoxyglucose PET imaging. One potential advantage of catabolizing glucose through glycolysis at a rate that exceeds bioenergetic need is that the growing cell can redirect the excess glycolytic end product pyruvate toward lipid synthesis. Such de novo lipid synthesis is necessary for membrane production and lipid-based posttranslational modification of proteins. A key enzyme linking glucose metabolism to lipid synthesis is ATP citrate lyase (ACL), which catalyzes the conversion of citrate to cytosolic acetyl-CoA. ACL inhibition by RNAi or the chemical inhibitor SB-204990 limits in vitro proliferation and survival of tumor cells displaying aerobic glycolysis. The same treatments also reduce in vivo tumor growth and induce differentiation.
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            Author and article information

            Affiliations
            [1 ]simpleDivision of Molecular Biotherapy, Cancer Chemotherapy Centre, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku Tokyo 135-8550, Japan
            [2 ]simpleDirector's Room, Cancer Chemotherapy Centre, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku Tokyo 135-8550, Japan
            Author notes
            [* ]Author for correspondence: tmashima@ 123456jfcr.or.jp
            [3]

            Takashi Tsuruo would have been the corresponding author had he lived to see the paper's publication

            Journal
            Br J Cancer
            British Journal of Cancer
            Nature Publishing Group
            0007-0920
            1532-1827
            07 April 2009
            28 April 2009
            05 May 2009
            : 100
            : 9
            : 1369-1372
            2694429
            6605007
            10.1038/sj.bjc.6605007
            19352381
            Copyright 2009, Cancer Research UK
            Categories
            Minireview

            Oncology & Radiotherapy

            lipid metabolism, fatty-acid synthase, acyl-coa synthetase

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