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浙江大学学报(医学版)  2021, Vol. 50 Issue (1): 23-31    DOI: 10.3724/zdxbyxb-2021-0033
专题报道     
胆固醇代谢与肿瘤
孟颖1,2(),王启扉1,2,吕志民1,2,*()
1.浙江大学医学院附属第一医院肝胆胰外科 浙江省胰腺疾病重点实验室,浙江 杭州 310003
2.浙江大学医学院转化医学研究院,浙江 杭州 310029
Cholesterol metabolism and tumor
MENG Ying1,2(),WANG Qifei1,2,LYU Zhimin1,2,*()
1. Zhejiang Provincial Key Laboratory of Pancreatic Disease,Department of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310003,China;
2. Institute of Translational Medicine,Zhejiang University School of Medicine,Hangzhou 310029,China
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摘要:

胆固醇是哺乳动物体内重要的脂质,是必不可少的膜结构成分。胆固醇稳态平衡对维持细胞和机体的生命活动至关重要,机体主要通过内源胆固醇的生物合成和外源胆固醇的摄取来获得胆固醇以维持自身稳态平衡。肿瘤细胞中胆固醇代谢异常活跃,导致其增殖、存活、侵袭、转移以及对肿瘤微环境的适应能力增强。靶向胆固醇合成、降低血浆胆固醇水平和胆固醇酯化的治疗策略将为肿瘤患者的治疗带来新的希望。本文总结了胆固醇代谢调节及其在肿瘤发生发展中的研究进展,并讨论了目前干扰胆固醇代谢的肿瘤治疗新方法。

关键词: 胆固醇代谢肿瘤治疗综述    
Abstract:

Cholesterol is an important lipid in the body of mammals and an essential component of membrane structures. Cholesterol homeostasis is critical for the maintenance of cellular and body activities, and is mainly regulated by the balance of de novo cholesterol biosynthesis and the exogenous cholesterol uptake. Aberrantly regulated cholesterol metabolism promotes tumor cell proliferation,survival,invasion and metastasis,and their adaptability into the tumor microenvironment. Therefore,targeting cholesterol biosynthesis and reduction of plasma cholesterol levels and cholesterol esterification will provide new strategies for cancer treatment. This review summarizes the current understanding in cholesterol homeostasis regulation and its function in the occurence and development of cancer,as well as current metabolism-targeted cancer treatments.

Key words: Cholesterol    Metabolism    Tumor    Therapy    Review
收稿日期: 2020-11-25 出版日期: 2021-05-16
CLC:  R73  
基金资助: 科技部重点研发计划(2020YFA0803300); 浙江省引进培育领军型创新创业团队(2019R01001)
通讯作者: 吕志民     E-mail: ymeng@zju.edu.cn;zhiminlu@zju.edu.cn
作者简介: 孟颖,博士后,主要从事胆固醇代谢及肿瘤发生发展相关研究; E-mail:ymeng@zju.edu.cn; https://orcid.org/0000-0002-1165-9009
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孟颖,王启扉,吕志民. 胆固醇代谢与肿瘤[J]. 浙江大学学报(医学版), 2021, 50(1): 23-31.

MENG Ying,WANG Qifei,LYU Zhimin. Cholesterol metabolism and tumor. J Zhejiang Univ (Med Sci), 2021, 50(1): 23-31.

链接本文:

http://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2021-0033        http://www.zjujournals.com/med/CN/Y2021/V50/I1/23

图1  胆固醇的生物合成
图 2  受体介导的外源胆固醇摄取
1 BROWN M S, RADHAKRISHNAN A, GOLDSTEIN J L . Retrospective on cholesterol homeostasis:the central role of scap[J]. Annu Rev Biochem, 2018, 87(1): 783-807.
doi: 10.1146/annurev-biochem-062917-011852
2 IKONEN E . Mechanisms for cellular cholesterol transport:defects and human disease[J]. Physiol Rev, 2006, 86(4): 1237-1261.
doi: 10.1152/physrev.00022.2005
3 YOSHIOKA Y,SASAKI J,YAMAMOTO M,et al.Quantitation by (1)H-NMR of dolichol,cholesterol and choline-containing lipids in extracts of normal and phathological thyroid tissue[J]. NMR Biomed,2000,13(7):377–383.DOI:10.1002/1099-1492(200011)13:7<377::aid-nbm658>3.0.co;2-e .
4 LISCUM L, FINER-MOORE J, STROUD R M, et al. Domain structure of 3-hydroxy-3-methylglutaryl coenzyme A reductase,a glycoprotein of the endop- lasmic reticulum[J]. J Biol Chem, 1985, 260(1): 522-530.
doi: 10.1016/S0021-9258(18)89764-2
5 KO C W, QU J, BLACK D D, et al. Regulation of intestinal lipid metabolism:current concepts and relevance to disease[J]. Nat Rev Gastroenterol Hepatol, 2020, 17(3): 169-183.
doi: 10.1038/s41575-019-0250-7
6 NELSON J K, KOENIS D S, SCHEIJ S, et al. EEPD1 Is a novel LXR target gene in macrophages which regulates ABCA1 abundance and cholesterol efflux[J]. Arterioscler Thromb Vasc Biol, 2017, 37(3): 423-432.
doi: 10.1161/ATVBAHA.116.308434
7 MENG Y, HEYBROCK S, NECULAI D, et al. Cholesterol handling in lysosomes and beyond[J]. Trends Cell Biol, 2020, 30(6): 452-466.
doi: 10.1016/j.tcb.2020.02.007
8 BROWN M S, GOLDSTEIN J L . A receptor-mediated pathway for cholesterol homeostasis[J]. Science, 1986, 232(4746): 34-47.
doi: 10.1126/science.3513311
9 MEYER J M, GRAF G A, VAN DER WESTHUYZEN D R . New developments in selective cholesteryl ester uptake[J]. Curr Opin Lipidology, 2013, 24(5): 386-392.
doi: 10.1097/MOL.0b013e3283638042
10 DAS A, BROWN M S, ANDERSON D D, et al. Three pools of plasma membrane cholesterol and their relation to cholesterol homeostasis [J/OL]. eLife, 2014, e02882.
doi: 10.7554/eLife.02882
11 GOLDSTEIN J L, BROWN M S . The LDL receptor[J]. ATVB, 2009, 29(4): 431-438.
doi: 10.1161/ATVBAHA.108.179564
12 LUO J, YANG H, SONG B L . Mechanisms and regulation of?cholesterol homeostasis[J]. Nat Rev Mol Cell Biol, 2020, 21(4): 225-245.
doi: 10.1038/s41580-019-0190-7
13 GLASS C, PITTMAN R C, CIVEN M, et al. Uptake of high-density lipoprotein-associated apoprotein A-I and cholesterol esters by 16 tissues of the rat in vivo and by adrenal cells and hepatocytes in vitro[J] . J Biol Chem, 1985, 260(2): 744-750.
doi: 10.1016/S0021-9258(20)71160-9
14 GLASS C, PITTMAN R C, WEINSTEIN D B, et al. Dissociation of tissue uptake of cholesterol ester from that of apoprotein A-I of rat plasma high density lipoprotein:selective delivery of cholesterol ester to liver,adrenal,and gonad[J]. Proc Natl Acad Sci USA, 1983, 80(17): 5435-5439.
doi: 10.1073/pnas.80.17.5435
15 NECULAI D, SCHWAKE M, RAVICHANDRAN M, et al. Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36[J]. Nature, 2013, 504(7478): 172-176.
doi: 10.1038/nature12684
16 HAMPTON R Y . A cholesterol toggle switch[J]. Cell Metab, 2008, 8(6): 451-453.
doi: 10.1016/j.cmet.2008.11.006
17 HORTON J D, SHAH N A, WARRINGTON J A, et al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes[J]. Proc Natl Acad Sci USA, 2003, 100(21): 12027-12032.
doi: 10.1073/pnas.1534923100
18 GOLDSTEIN J L, DEBOSE-BOYD R A, BROWN M S . Protein sensors for membrane sterols[J]. Cell, 2006, 124(1): 35-46.
doi: 10.1016/j.cell.2005.12.022
19 BOVENGA F, SABBà C, MOSCHETTA A . Uncoupling nuclear receptor LXR and cholesterol metabolism in cancer[J]. Cell Metab, 2015, 21(4): 517-526.
doi: 10.1016/j.cmet.2015.03.002
20 LI C S, WU W, XIE K K, et al. HMGCR is up-regulated in gastric cancer and promotes the growth and migration of the cancer cells[J]. Gene, 2016, 587(1): 42-47.
doi: 10.1016/j.gene.2016.04.029
21 QIU Z, YUAN W, CHEN T, et al. HMGCR positively regulated the growth and migration of glioblastoma cells[J]. Gene, 2016, 576(1): 22-27.
doi: 10.1016/j.gene.2015.09.067
22 ASHIDA S, KAWADA C, INOUE K . Stromal regulation of prostate cancer cell growth by mevalonate pathway enzymes HMGCS1 and HMGCR[J]. Oncol Lett, 2017, 14(6): 6533-6542.
doi: 10.3892/ol.2017.7025
23 KONG Y, CHENG L, MAO F, et al. Inhibition of cholesterol biosynthesis overcomes enzalutamide resistance in castration-resistant prostate cancer (CRPC)[J]. J Biol Chem, 2018, 293(37): 14328-14341.
doi: 10.1074/jbc.RA118.004442
24 LEE J S, ROBERTS A, JUAREZ D, et al. Statins enhance efficacy of venetoclax in blood cancers[J]. Sci Transl Med, 2018, 10(445): eaaq1240.
doi: 10.1126/scitranslmed.aaq1240
25 YANG J, WANG L, JIA R . Role of de novo cholesterol synthesis enzymes in cancer[J] . J Cancer, 2020, 11(7): 1761-1767.
doi: 10.7150/jca.38598
26 BROWN D N, CAFFA I, CIRMENA G, et al. Squalene epoxidase is a bona fide oncogene by amplification with clinical relevance in breast cancer[J]. Sci Rep, 2016, 6(1): 19435.
doi: 10.1038/srep19435
27 CIRMENA G, FRANCESCHELLI P, ISNALDI E, et al. Squalene epoxidase as a promising metabolic target in cancer treatment[J]. Cancer Lett, 2018, 13-20.
doi: 10.1016/j.canlet.2018.03.034
28 LIU D, WONG C C, FU L, et al. Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target [J/OL]. Sci Transl Med, 2018, 10(437): eaap9840.
doi: 10.1126/scitranslmed.aap9840
29 ZHOU T, ZHAN J, FANG W, et al. Serum low-density lipoprotein and low-density lipoprotein expression level at diagnosis are favorable prognostic factors in patients with small-cell lung cancer (SCLC)[J]. BMC Cancer, 2017, 17(1): 269.
doi: 10.1186/s12885-017-3239-z
30 GALLAGHER E J, ZELENKO Z, NEEL B A, et al. Elevated tumor LDLR expression accelerates LDL cholesterol-mediated breast cancer growth in mouse models of hyperlipidemia[J]. Oncogene, 2017, 36(46): 6462-6471.
doi: 10.1038/onc.2017.247
31 GUILLAUMOND F, BIDAUT G, OUAISSI M, et al. Cholesterol uptake disruption,in association with chemotherapy,is a promising combined metabolic therapy for pancreatic adenocarcinoma[J]. Proc Natl Acad Sci USA, 2015, 112(8): 2473-2478.
doi: 10.1073/pnas.1421601112
32 GUO D, REINITZ F, YOUSSEF M, et al. An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway[J]. Cancer Discov, 2011, 1(5): 442-456.
doi: 10.1158/2159-8290.CD-11-0102
33 YUE S, LI J, LEE S Y, et al. Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressi- veness[J]. Cell Metab, 2014, 19(3): 393-406.
doi: 10.1016/j.cmet.2014.01.019
34 MENARD J A, CHRISTIANSON H C, KUCHARZEWSKA P, et al. Metastasis stimulation by hypoxia and acidosis-induced extracellular lipid uptake is mediated by proteoglycan-dependent endocytosis[J]. Cancer Res, 2016, 76(16): 4828-4840.
doi: 10.1158/0008-5472.CAN-15-2831
35 ZELCER N, HONG C, BOYADJIAN R, et al. LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor[J]. Science, 2009, 325(5936): 100-104.
doi: 10.1126/science.1168974
36 AYLON Y, OREN M . The Hippo pathway,p53 and cholesterol[J]. Cell Cycle, 2016, 15(17): 2248-2255.
doi: 10.1080/15384101.2016.1207840
37 XU D, WANG Z, XIA Y, et al. The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis[J]. Nature, 2020, 580(7804): 530-535.
doi: 10.1038/s41586-020-2183-2
38 OHTAKI S, WANIBUCHI M, KATAOKA-SASAKI Y, et al. ACTC1 as an invasion and prognosis marker in glioma[J]. JNS, 2017, 126(2): 467-475.
doi: 10.3171/2016.1.JNS152075
39 IKONEN E . Cellular cholesterol trafficking and compartmentalization[J]. Nat Rev Mol Cell Biol, 2008, 9(2): 125-138.
doi: 10.1038/nrm2336
40 LIN C Y, GUSTAFSSON J ? . Targeting liver X receptors in cancer therapeutics[J]. Nat Rev Cancer, 2015, 15(4): 216-224.
doi: 10.1038/nrc3912
41 TAO R, XIONG X, DEPINHO R A, et al. Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6[J]. J Lipid Res, 2013, 54(10): 2745-2753.
doi: 10.1194/jlr.M039339
42 FLAVENY C A, GRIFFETT K, EL-GENDY B E D M, et al. Broad anti-tumor activity of a small molecule that selectively targets the warburg effect and lipogenesis[J]. Cancer Cell, 2015, 28(1): 42-56.
doi: 10.1016/j.ccell.2015.05.007
43 RIOLS F,BERTRAND-MICHEL J. Analysis of oxysterols[J]. Methods Mol Biol,2018,1730:267-275.DOI:10.1007/978-1-4939-7592-1_19 .
44 CHEN J, YE Y, LIU P, et al. Suppression of T cells by myeloid-derived suppressor cells in cancer[J]. Human Immunol, 2017, 78(2): 113-119.
doi: 10.1016/j.humimm.2016.12.001
45 SAXENA K, SHIPLEY G G . Structural studies of detergent-solubilized and vesicle-reconstituted low-density lipoprotein (LDL) receptor[J]. Biochemi- stry, 1997, 36(50): 15940-15948.
doi: 10.1021/bi971579p
46 SIVAPRASAD U, ABBAS T, DUTTA A . Differential efficacy of 3-hydroxy-3-methylglutaryl CoA reductase inhibitors on the cell cycle of prostate cancer cells[J]. Mol Cancer Ther, 2006, 5(9): 2310-2316.
doi: 10.1158/1535-7163.MCT-06-0175
47 SONG X, LIU B C, LU X Y, et al. Lovastatin inhibits human B lymphoma cell proliferation by reducing intracellular ROS and TRPC6 expression[J]. BBA- Mol Cell Res, 2014, 1843(5): 894-901.
doi: 10.1016/j.bbamcr.2014.02.002
48 TU Y S, KANG X L, ZHOU J G, et al. Involvement of Chk1–Cdc25A-cyclin A/CDk2 pathway in simvastatin induced S-phase cell cycle arrest and apoptosis in multiple myeloma cells[J]. Eur J Pharmacol, 2011, 670(2-3): 356-364.
doi: 10.1016/j.ejphar.2011.09.031
49 MENTER D G, RAMSAUER V P, HARIRFOROOSH S, et al. Differential effects of pravastatin and simvastatin on the growth of tumor cells from different organ sites [J/OL]. PLoS One, 2011, 6(12): e28813.
doi: 10.1371/journal.pone.0028813
50 XIA Y, XIE Y, YU Z, et al. The Mevalonate pathway is a druggable target for vaccine adjuvant discovery [J/OL]. Cell, 2018, 175(4): 1059-1073.e21.
doi: 10.1016/j.cell.2018.08.070
51 ABDEL-RAHMAN O . Statin treatment and outcomes of metastatic pancreatic cancer:a pooled analysis of two phase Ⅲ studies[J]. Clin Transl Oncol, 2019, 21(6): 810-816.
doi: 10.1007/s12094-018-1992-3
52 BR?NVALL E, EKBERG S, ELORANTA S, et al. Statin use is associated with improved survival in multiple myeloma:A Swedish population‐based study of 4315 patients[J]. Am J Hematol, 2020, 95(6): 652-661.
doi: 10.1002/ajh.25778
53 CARDWELL C R, HICKS B M, HUGHES C, et al. Statin use after colorectal cancer diagnosis and survival:a population-based cohort study[J]. JCO, 2014, 32(28): 3177-3183.
doi: 10.1200/JCO.2013.54.4569
54 HAN J Y, LEE S H, YOO N J, et al. A randomized phase II study of gefitinib plus simvastatin versus gefitinib alone in previously treated patients with advanced non-small cell lung cancer[J]. Clin Cancer Res, 2011, 17(6): 1553-1560.
doi: 10.1158/1078-0432.CCR-10-2525
55 LEE Y, LEE K H, LEE G K, et al. Randomized phase Ⅱ study of afatinib plus simvastatin versus afatinib alone in previously treated patients with advanced nonadenocarcinomatous non-small cell lung cancer[J]. Cancer Res Treat, 2017, 49(4): 1001-1011.
doi: 10.4143/crt.2016.546
56 DUNCAN R E, EL-SOHEMY A, ARCHER M C . Statins and the risk of cancer[J]. JAMA, 2006, 295(23): 2720.
doi: 10.1001/jama.295.23.2720-a
57 KIM S T, KANG J H, LEE J, et al. Simvastatin plus capecitabine–cisplatin versus placebo plus capecita- bine–cisplatin in patients with previously untreated advanced gastric cancer:A double-blind randomised phase 3 study[J]. Eur J Cancer, 2014, 50(16): 2822-2830.
doi: 10.1016/j.ejca.2014.08.005
58 FARMER J A. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis (the SEAS trial)[J]. Curr Atheroscler Rep,2009,11(2):82–83 .
59 JOSEPH L, ROBINSON J G . Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and the future of lipid lowering therapy[J]. Prog Cardio- vascular Dis, 2015, 58(1): 19-31.
doi: 10.1016/j.pcad.2015.04.004
60 NOWAK C, ?RNL?V J . A Mendelian randomization study of the effects of blood lipids on breast cancer risk[J]. Nat Commun, 2018, 9(1): 3957.
doi: 10.1038/s41467-018-06467-9
61 REVILLA G, CEDó L, TONDO M, et al. LDL,HDL and endocrine-related cancer:From pathogenic mechanisms to therapies[J/OL]. Seminars Cancer Biol, 2020,
doi: 10.1016/j.semcancer.2020.11.012
62 LINCOFF A M, NICHOLLS S J, RIESMEYER J S, et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease[J]. N Engl J Med, 2017, 376(20): 1933-1942.
doi: 10.1056/NEJMoa1609581
63 SCHWARTZ G G, OLSSON A G, ABT M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome[J]. N Engl J Med, 2012, 367(22): 2089-2099.
doi: 10.1056/NEJMoa1206797
64 BARTER P J, CAULFIELD M, ERIKSSON M, et al. Effects of torcetrapib in patients at high risk for coronary events[J]. N Engl J Med, 2007, 357(21): 2109-2122.
doi: 10.1056/NEJMoa0706628
65 BOWMAN L, HOPEWELL J C, CHEN F, et al. effects of anacetrapib in patients with atherosclerotic vascular disease[J]. N Engl J Med, 2017, 377(13): 1217-1227.
doi: 10.1056/NEJMoa1706444
66 Kamanna S V, Kashyap L M . Mechanism of action of niacin[J]. Am J Cardiology, 2008, 101(8): S20-S26.
doi: 10.1016/j.amjcard.2008.02.029
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