类泛素化修饰Neddylation及MLN4924抗肿瘤作用研究进展

doi:10.3969/j.issn.1673-8640.2019.04.018

摘要/Abstract

摘要：

Neddylation修饰是近年来发现的新型蛋白质翻译后修饰,可以广泛地调节生物学过程,如细胞周期、信号传导和免疫识别等。Neddylation修饰在多种肿瘤细胞中过度活化并促进肿瘤的发生、发展,如阻断此修饰通路具有显著的抗肿瘤效果。Neddylation修饰的小分子抑制剂MLN4924可使肿瘤细胞发生细胞周期阻滞、衰老和凋亡,同时还有抑制肿瘤血管生成等作用。文章对Neddylation修饰及其抑制剂MLN4924的抗肿瘤机制作一综述。

关键词: Neddylation修饰, 分子靶向药物, MLN4924, 抗肿瘤机制

Abstract:

Neddylation modification is a new type of protein posttranslational modification discovered in recent years. A wide range of biological processes,including cell cycle,signal transduction and immune recognition,can be regulated. Neddylation modification is highly activated in many cancer cells and promotes cancer development. Blocking this modification has anti-tumor effect. MLN4924,small molecule inhibitor of Neddylation modification,can lead to the induction of cell cycle arrest,apoptosis,senescence and the inhibition of tumor angiogenesis. The review focuses on the mechanism and inhibitor of Neddylation modification and MLN4924.

Key words: Neddylation modification, Molecular-targetd drug, MLN4924, Anti-tumor mechanism

中图分类号:

R446.1

刘越, 王诗雯, 张艳梅, 赵虎. 类泛素化修饰Neddylation及MLN4924抗肿瘤作用研究进展[J]. 检验医学, 2019, 34(4): 370-374.

LIU Yue, WANG Shiwen, ZHANG Yanmei, ZHAO Hu. Research progress of ubiquitin-like modification of Neddylation and MLN4924 for the treatment of tumors[J]. Laboratory Medicine, 2019, 34(4): 370-374.

图/表 1

参考文献 42

[1]	SCHÖNICHEN A,WEBB B A,JACOBSON M P,et al. Considering protonation as a posttranslational modification regulating protein structure and function[J]. Annu Rev Biophys,2013,42:289-314.
[2]	LEACH M D,BROWN A J.Posttranslational modifications of proteins in the pathobiology of medically relevant fungi[J]. Eukaryot Cell,2012,11(2):98-108.
[3]	MERGNER J,SCHWECHHEIMER C.The NEDD8 modification pathway in plants[J]. Front Plant Sci,2014,5:103.
[4]	LUCARIELLO A,TRABUCCO E,SELLITTO C,et al.Localization and modulation of NEDD8 protein in the human placenta[J]. In Vivo,2013,27(4):501-506.
[5]	WANG Y,LUO Z,PAN Y,et al.Targeting protein neddylation with an NEDD8-activating enzyme inhibitor MLN4924 induced apoptosis or senescence in human lymphoma cells[J]. Cancer Biol Ther,2015,16(3):420-429.
[6]	JIANG Y,JIA L.Neddylation pathway as a novel anti-cancer target:mechanistic investigation and therapeutic implication[J]. Anticancer Agents Med Chem,2015,15(9):1127-1133.
[7]	KANDALA S,KIM I M,SU H.Neddylation and deneddylation in cardiac biology[J]. Am J Cardiovasc Dis,2014,4(4):140-158.
[8]	SCOTT D C,RHEE D Y,DUDA D M,et al. Two distinct types of E3 ligases work in unison to regulate substrate ubiquitylation[J]. Cell,2016,166(5):1198-1214. e24.
[9]	BENNETT E J,RUSH J,GYGI S P,et al.Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics[J]. Cell,2010,143(6):951-965.
[10]	CAMUS S,MÉNENDEZ S,FERNANDES K,et al. The p53 isoforms are differentially modified by Mdm2[J]. Cell Cycle,2012,11(8):1646-1655.
[11]	MARINE J C,LOZANO C.Mdm2-mediated ubiquitylation: p53 and beyond[J]. Cell Death Differ,2010,17(1):93-102.
[12]	BROOKS C L,GU W. p53 ubiquitination:Mdm2 and beyond[J]. Mol Cell,2006,21(3):307-315.
[13]	EMBADE N,FERNÁNDEZ-RAMOS D,VARELA-REY M,et al. Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation[J]. Hepatology,2012,55(4):1237-1248.
[14]	GAO F,CHENG J,SHI T,et al.Neddylation of a breast cancer-associated protein recruits a classⅢ histone deacetylase that represses NF kappa B-dependent transcription[J]. Nat Cell Biol,2006,8(10):1171-1177.
[15]	STICKLE N H,CHUNG J,KLCO J M,et al.pVHL modification by NEDD8 is required for fibronectin matrix assembly and suppression of tumor development[J]. Mol Cell Biol,2004,24(8):3251-3261.
[16]	ZUO W,HUANG F,CHIANG Y J,et al.c-Cbl-mediated neddylation antagonizes ubiquitination and degradation of the TGF-β type Ⅱ receptor[J]. Mol Cell,2013,49(3):499-510.
[17]	LIU N,ZHANG J,YANG X,et al.HDM2 promotes NEDDylation of hepatitis B virus HBx to enhance its stability and function[J]. J Virol,2017,91(16):e00340-17.
[18]	KIM W,BENNETT E J,HUTTLIN E L,et al.Systematic and quantitative assessment of the ubiquitin-modified proteome[J]. Mol Cell,2011,44(2):325-340.
[19]	ZHAO Y, MORGAN M A, SUN Y.Targeting Neddylation pathways to inactivate cullin-RING ligases for anticancer therapy[J]. Antioxid Redox Signal, 2014,21(17):2383-2400.
[20]	LI L,WANG M,YU G,et al. Overactivated neddylation pathway as a therapeutic target in lung cancer[J]. J Natl Cancer Inst,2014,106(6):dju083.
[21]	CHEN P,HU T,LIANG Y,et al.Synergistic inhibition of autophagy and neddylation pathways as a novel therapeutic approach for targeting liver cancer[J]. Oncotarget,2015,6(11):9002-9017.
[22]	GAO Q,YU G Y,SHI J Y,et al.Neddylation pathway is up-regulated in human intrahepatic cholangiocarcinoma and serves as a potential therapeutic target[J]. Oncotarget,2014,5(17):7820-7832.
[23]	HUA W,LI C,YANG Z,et al.Suppression of glioblastoma by targeting the overactivated protein neddylation pathway[J]. Neuro Oncol,2015,17(10):1333-1343.
[24]	XIE P,YANG J P,CAO Y,et al.Promoting tumorigenesis in nasopharyngeal carcinoma,NEDD8 serves as a potential theranostic target[J]. Cell Death Dis,2017,8(6):e2834.
[25]	WANG X,ZHANG W,YAN Z,et al.Radiosensitization by the investigational NEDD8-activating enzyme inhibitor MLN4924 (pevonedistat) in hormone-resistant prostate cancer cells[J]. Oncotarget,2016,7(25):38380-38391.
[26]	WANG J,WANG S,ZHANG W,et al.Targeting neddylation pathway with MLN4924 (Pevonedistat) induces NOXA-dependent apoptosis in renal cell carcinoma[J]. Biochem Biophys Res Commun,2017,490(4):1183-1188.
[27]	BARBIER-TORRES L,DELGADO T C,GARCÍA-RODRÍGUEZ J L,et al. Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer[J]. Oncotarget,2015,6(4):2509-2523.
[28]	WATSON I R,IRWIN M S,OHH M.NEDD8 pathways in cancer,Sine Quibus Non[J]. Cancer Cell,2011,19(2):168-176.
[29]	PAN Z Q,KENTSIS A,DIAS D C,et al.Nedd8 on cullin: building an expressway to protein destruction[J]. Oncogene,2004,23(11):1985-1997.
[30]	PANDEY D,HORI D,KIM J H,et al.NEDDylation promotes endothelial dysfunction: a role for HDAC2[J]. J Mol Cell Cardiol,2015,81:18-22.
[31]	ZHANG Y,LUO Q,WANG N,et al.LRG1 suppresses the migration and invasion of hepatocellular carcinoma cells[J]. Med Oncol,2015,32(5):146.
[32]	MILHOLLEN M,THOMAS M,NARAYANAN U,et al.Treatment-emergent mutations in NAEβ confer resistance to the NEDD8-activating enzyme inhibitor MLN4924[J]. Cancer Cell,2012,21(3):388-401.
[33]	SOUCY T A,SMITH P G,MILHOLLEN M A,et al.An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer[J]. Nature,2009,458(7239):732-736.
[34]	SARANTOPOULOS J,SHAPIRO G I,COHEN R B,et al.Phase Ⅰ study of the investigational NEDD8-activating enzyme inhibitor pevonedistat(TAK-924/MLN4924) in patients with advanced solid tumors[J]. Clin Cancer Res,2016,22(4):847-857.
[35]	SHAH J J,JAKUBOWIAK A J,O'CONNOR O A,et al. Phase Ⅰ study of the novel investigational NEDD8-activating enzyme inhibitor pevonedistat(MLN4924) in patients with relapsed/refractory multiple myeloma or lymphoma[J]. Clin Cancer Res,2016,22(1):34-43.
[36]	LI L,LIU B,DONG T,et al.Neddylation pathway regulates the proliferation and survival of macrophages[J]. Biochem Biophys Res Commun,2013,432(3):494-498.
[37]	MILHOLLEN M A,NARAYANAN U,SOUCY T A,et al.Inhibition of NEDD8-activating enzyme induces rereplication and apoptosis in human tumor cells consistent with deregulating CDT1 turnover[J]. Cancer Res,2011,71(8):3042-3051.
[38]	LAN H,TANG Z,JIN H,et al.Neddylation inhibitor MLN4924 suppresses growth and migration of human gastric cancer cells[J]. Sci Rep,2016,6:24218.
[39]	ZHANG Y,SHI C C,ZHANG H P,et al.MLN4924 suppresses neddylation and induces cell cycle arrest,senescence,and apoptosis in human osteosarcoma[J]. Oncotarget,2016,7(29):45263-45274.
[40]	HUANG J,ZHOU Y,THOMAS G S,et al.NEDD8 inhibition overcomes CKS1B-induced drug resistance by upregulation of p21 in multiple myeloma[J]. Clin Cancer Res,2015,21(24):5532-5542.
[41]	BUHRMANN C,KRAEHE P,LUEDERS C,et al.Curcumin suppresses crosstalk between colon cancer stem cells and stromal fibroblasts in the tumor microenvironment: potential role of EMT[J]. PLoS One,2014,9(9):e107514.
[42]	YAO W T,WU J F,YU G Y,et al.Suppression of tumor angiogenesis by targeting the protein neddylation pathway[J]. Cell Death Dis,2014,5:e1059.