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      Role of de novo cholesterol synthesis enzymes in cancer

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          Abstract

          Despite extensive research in the cancer field, cancer remains one of the most prevalent diseases. There is an urgent need to identify specific targets that are safe and effective for the treatment of cancer. In recent years, cancer metabolism has come into the spotlight in cancer research. Lipid metabolism, especially cholesterol metabolism, plays a critical role in membrane synthesis as well as lipid signaling in cancer. This review focuses on the contribution of the de novo cholesterol synthesis pathway to tumorigenesis, cancer progression and metastasis. In conclusion, cholesterol metabolism could be an effective target for novel anticancer treatment.

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          Most cited references55

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          On the origin of cancer cells.

          O WARBURG (1956)
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            The Role of Cholesterol in Cancer.

            The roles played by cholesterol in cancer development and the potential of therapeutically targeting cholesterol homeostasis is a controversial area in the cancer community. Several epidemiologic studies report an association between cancer and serum cholesterol levels or statin use, while others suggest that there is not one. Furthermore, the Cancer Genome Atlas (TCGA) project using next-generation sequencing has profiled the mutational status and expression levels of all the genes in diverse cancers, including those involved in cholesterol metabolism, providing correlative support for a role of the cholesterol pathway in cancer development. Finally, preclinical studies tend to more consistently support the role of cholesterol in cancer, with several demonstrating that cholesterol homeostasis genes can modulate development. Because of space limitations, this review provides selected examples of the epidemiologic, TCGA, and preclinical data, focusing on alterations in cholesterol homeostasis and its consequent effect on patient survival. In melanoma, this focused analysis demonstrated that enhanced expression of cholesterol synthesis genes was associated with decreased patient survival. Collectively, the studies in melanoma and other cancer types suggested a potential role of disrupted cholesterol homeostasis in cancer development but additional studies are needed to link population-based epidemiological data, the TCGA database results, and preclinical mechanistic evidence to concretely resolve this controversy. Cancer Res; 76(8); 2063-70. ©2016 AACR.
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              Liver X receptors in lipid signalling and membrane homeostasis

              Liver X receptors α and β (LXRα and LXRβ) are nuclear receptors with pivotal roles in the transcriptional control of lipid metabolism. Transcriptional activity of LXRs is induced in response to elevated cellular levels of cholesterol. LXRs bind to and regulate the expression of genes that encode proteins involved in cholesterol absorption, transport, efflux, excretion and conversion to bile acids. The coordinated, tissue-specific actions of the LXR pathway maintain systemic cholesterol homeostasis and regulate immune and inflammatory responses. LXRs also regulate fatty acid metabolism by controlling the lipogenic transcription factor sterol regulatory element-binding protein 1c and regulate genes that encode proteins involved in fatty acid elongation and desaturation. LXRs exert important effects on the metabolism of phospholipids, which, along with cholesterol, are major constituents of cellular membranes. LXR activation preferentially drives the incorporation of polyunsaturated fatty acids into phospholipids by inducing transcription of the remodelling enzyme lysophosphatidylcholine acyltransferase 3. The ability of the LXR pathway to couple cellular sterol levels with the saturation of fatty acids in membrane phospholipids has implications for several physiological processes, including lipoprotein production, dietary lipid absorption and intestinal stem cell proliferation. Understanding how LXRs regulate membrane composition and function might provide new therapeutic insight into diseases associated with dysregulated lipid metabolism, including atherosclerosis, diabetes mellitus and cancer.
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                Author and article information

                Journal
                J Cancer
                J Cancer
                jca
                Journal of Cancer
                Ivyspring International Publisher (Sydney )
                1837-9664
                2020
                17 January 2020
                : 11
                : 7
                : 1761-1767
                Affiliations
                [1 ]Department of Ophthalmology, Ninth People's Hospital of Shanghai, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
                [2 ]Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
                Author notes
                ✉ Corresponding authors: Renbing Jia, renbingjia@ 123456sjtu.edu.cn and Lihua Wang, wanglihua0902@ 123456126.com . Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhi Zao Ju Road, Shanghai 200011, China

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                jcav11p1761
                10.7150/jca.38598
                7052851
                32194787
                5b13eb00-63fe-4085-9aff-0bf9a85d4d95
                © The author(s)

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 21 July 2019
                : 30 November 2019
                Categories
                Review

                Oncology & Radiotherapy
                metabolic reprogramming,de novo cholesterol synthesis,cancer progress

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