Conceptualizi...y-to-practice_Hang Zhang.pdf
《Conceptualizi...y-to-practice_Hang Zhang.pdf》由会员分享,可在线阅读,更多相关《Conceptualizi...y-to-practice_Hang Zhang.pdf(6页珍藏版)》请在咨信网上搜索。
1、Cancer Biol Med 2023.doi:10.20892/j.issn.2095-3941.2022.0767PERSPECTIVEConceptualizing the complexity of ferroptosis to treat triple-negative breast cancer:theory-to-practiceHang Zhang*,Fan Yang*,Yi Xiao,Yi-Zhou Jiang,Zhi-Ming ShaoKey Laboratory of Breast Cancer in Shanghai,Department of Breast Surg
2、ery,Fudan University Shanghai Cancer Center;Department of Oncology,Shanghai Medical College,Fudan University,Shanghai 200032,ChinaFerroptosis,a type of regulated cell death named one dec-ade ago,is a unique type driven by lipid peroxidation in an iron-dependent manner.Ferroptosis differs radically f
3、rom apoptosis and other regulated forms of cell death in both morphology and molecular underpinning.Ferroptosis can be triggered by a variety of physiologic conditions and patho-logic stresses.There has been growing interest in ferroptosis in recent years,and research on ferroptosis is productive.Th
4、e existing evidence has shown that ferroptosis is closely related to cancer initiation,progression,and suppression.Thus,fer-roptosis has shown promising potential in cancer therapies.Inducing ferroptosis in tumors and the combination of fer-roptosis inducers with other therapies may overcome drug re
5、sistance during cancer treatment.Because of the intricate network regulating ferroptosis-related pathways,drugs tar-geting ferroptosis are diverse and complicated.Thus,deci-phering the complexity of ferroptosis and precisely targeting ferroptosis are needed.Heterogeneity of ferroptosis-related pathw
6、ays among tumorsFerroptosis is executed by membrane oxidative damage with increased lipid peroxidation.Peroxidation of polyunsatu-rated fatty acids(PUFAs)is essential for triggering ferroptosis.Multiple metabolic pathways evolve during the process of ferroptosis.Ferroptosis-promoting pathways includ
7、e the lipid,iron,and mitochondrial metabolism pathways(Figure 1).PUFA peroxidation can occur through a series of enzyme catalysis in the lipid metabolism pathway.Acyl-CoA(coen-zyme)synthetase long-chain family member 4(ACSL4)catalyzes the ligation of PUFAs with CoA and generates CoA-PUFAs.CoA-PUFAs
8、are esterified by lysophosphatidylcholine acyltransferase 3(LPCAT3)to form phospholipids contain-ing polyunsaturated fatty acids(PE-PUFAs).PE-PUFAs are mainly catalyzed by autoxidation and are prone to peroxidi-zation by lipoxygenase(ALOX)or cytochrome P450 oxidore-ductase(POR)into lipid hydroperoxi
9、des.The generation of lipid hydroperoxides promotes ferroptosis initiation.Iron metabolism has multiple processes,including iron absorp-tion,storage,utilization,and efflux.Indeed,cells maintain a relatively labile iron pool via these processes;however,can-cer cells have dysregulated iron metabolism
10、and an increased labile iron pool.Iron increases ALOX activity.The free ferrous iron in the labile iron pool also participates in the Fenton reaction to generate free radicals and mediate lipid peroxi-dation.Mitochondrial metabolism is another pathway that promotes ferroptosis.Mitochondria,as the si
11、te of multiple metabolic pathways in the cell,are the main source of cellu-lar reactive oxygen species(ROS).The electrons leaked from the electron transport chain(ETC)complexes can be used to generate hydrogen peroxide(H2O2).H2O2 reacts with ferrous iron to generate hydroxyl radicals(OH),which leads
12、 to lipid peroxidation1.In addition,anaplerotic reactions that replen-ish the tricarboxylic acid(TCA)cycle,such as glutaminolysis,promote ferroptosis by increasing fatty acid biosynthesis and electron leakage1.Cells have developed ways to defend against ferroptosis,including the glutathione(GSH),ubi
13、quinol(CoQH2),and*These authors contributed equally to this work.Correspondence to:Zhi-Ming ShaoE-mail:Received January 4,2023;accepted January 5,2023Available at www.cancerbiomed.org2023 Cancer Biology&Medicine.Creative Commons Attribution-NonCommercial 4.0 International LicenseCancer Biol Med Vol
14、20,No 2 February 2023 99tetrahydrobiopterin(BH4)metabolism pathways(Figure 1).Cancer cells obtain cystine through System Xc-,which is embedded in the cell membrane,during GSH metabolism.Then,cystine is reduced to cysteine and catalyzed by glutamic acid-cysteine ligase(GCL)and glutathione synthase(GS
15、S)to synthesize GSH.Glutathione peroxidase 4(GPX4),a regulator of ferroptosis,uses GSH as a cofactor to catalyze lipid peroxide reduction and prevent ferroptosis.The FSP1(ferroptosis sup-pressor protein 1)-CoQH2 axis is another pathway that pre-vents ferroptosis.FSP1 is recruited to the plasma membr
16、ane,acts as an oxidoreductase,and reduces ubiquinone(known as CoQ)to CoQH2,which traps lipid peroxyl radicals and inhib-its lipid peroxidation.The BH4-DHFR(dihydrofolate reduc-tase)axis is a GPX4-independent mechanism for ferroptosis regulation.BH4 is an antioxidant capable of trapping lipid peroxid
17、e-free radicals.BH4 undergoes redox cycling through DHFR to protect lipid membranes from autoxidation.BH4 synthesis is a critical pathway involved in GPX4 inhibition.Energy-related metabolism also has a role in regulating ferroptosis.Several cellular energy metabolism pathways Lipid metabolismIron m
18、etabolismMitochondrial metabolismRosiglitazoneACLACACAFASNFADS1/2Labile iron poolCitratePUFAIron reductionIron influxFe3+Fe2+O2.-H2O2OHOHFeFeFeFeFeFeFeFeFeFeFeFeGlutamineTCA cycleLipophagyATPAMPKPADPACCPUFAOXPHOSZileutonMK886LOXBlock-1ALOXROSACSL4LPCAT3Iron utilizationFerritinophagyPUFA-PELOOHPUFA-C
19、oALipid dropletFenton reactionFenton reactionBSOFerritinHaemFerroptosisprogressD-PUFA MUFAPUFAOxPEGSH metabolismNADPHNADP+system Xcp53ErastinSorafenibSulfasalazineBH4 metabolismCoQH2 metabolismStatinsLOOHIsopentenylpyrophosphateHMG-CoABCNUTranssulfurationpathwayMevalonatepathwayNADPHNADP+CoQCoQH2LOH
20、BSOiFSP1FIIN56GSSGCLGSHcysGSSGGSRGPX4FSP1GTPRSL3aFIN56ML162ML210GCH1DHFRMTXNADPHNADP+BH4BH2Figure 1 Overview of the regulatory network of ferroptosis.Schematic description of regulated pathways in ferroptosis,including three pro-moting mechanisms and three defense mechanisms.Inhibitors of ferroptosi
21、s-related pathways are included.ATP citrate lyase(ACL);acetyl-CoA(ACACA);fatty acid synthase(FASN);fatty acid desaturase(FADS);polyunsaturated fatty acid(PUFA);acyl-CoA synthetase long-chain family member 4(ACSL4);lysophosphatidylcholine acyltransferase 3(LPCAT3);phospholipids containing polyunsatur
22、ated fatty acids(PE-PUFAs);lipoxy-genase(ALOX);reactive oxygen species(ROS);lipid hydroperoxides(LOOH);hydroxyl radical(OH);tricarboxylic acid(TCA);oxidative phosphoryl-ation(OXPHOS);hydrogen peroxide(H2O2);adenosine monophosphate-activated protein kinase(AMPK);acetyl-CoA carboxylase(ACC);oxidized p
23、hosphatidylethanolamine(OxPE);glutathione(GSH);glutathione synthase(GSS);glutamic acid-cysteine ligase(GCL);cystine(cys);glutathione disulfide(GSSG);glutathione-disulfide reductase(GSR);lipid alcohol(LOH);ubiquinol(CoQH2);ubiquinone(CoQ);3-hydroxy-3-methylglutarylco-enzyme A(HMG-CoA);ferroptosis sup
24、pressor protein 1(FSP1);GTP cyclohydrolase 1(GCH1);tetrahydrobiopterin(BH4);dihydrobiopterin(BH2);dihydrofolate reductase(DHFR);deuterated polyunsaturated fatty acid(D-PUFA);monounsaturated fatty acid(MUFA).100 Zhang et al.Applying ferroptosis to treat breast cancerincluding glycolysis,pentose phosp
25、hate pathway(PPP)and TCA cycle are closely associated with oxidized phosphati-dylethanolamine(OxPE)biosynthesis and the generation of reducing substances.Mitochondria,as the energy power-house in cells,coordinate various metabolic processes and have a key role in ferroptosis.Mitochondria generate RO
- 配套讲稿:
如PPT文件的首页显示word图标,表示该PPT已包含配套word讲稿。双击word图标可打开word文档。
- 特殊限制:
部分文档作品中含有的国旗、国徽等图片,仅作为作品整体效果示例展示,禁止商用。设计者仅对作品中独创性部分享有著作权。
- 关 键 词:
- Conceptualizi.y-to-practice_Hang Zhang Conceptualizi to practice_Hang
1、咨信平台为文档C2C交易模式,即用户上传的文档直接被用户下载,收益归上传人(含作者)所有;本站仅是提供信息存储空间和展示预览,仅对用户上传内容的表现方式做保护处理,对上载内容不做任何修改或编辑。所展示的作品文档包括内容和图片全部来源于网络用户和作者上传投稿,我们不确定上传用户享有完全著作权,根据《信息网络传播权保护条例》,如果侵犯了您的版权、权益或隐私,请联系我们,核实后会尽快下架及时删除,并可随时和客服了解处理情况,尊重保护知识产权我们共同努力。
2、文档的总页数、文档格式和文档大小以系统显示为准(内容中显示的页数不一定正确),网站客服只以系统显示的页数、文件格式、文档大小作为仲裁依据,平台无法对文档的真实性、完整性、权威性、准确性、专业性及其观点立场做任何保证或承诺,下载前须认真查看,确认无误后再购买,务必慎重购买;若有违法违纪将进行移交司法处理,若涉侵权平台将进行基本处罚并下架。
3、本站所有内容均由用户上传,付费前请自行鉴别,如您付费,意味着您已接受本站规则且自行承担风险,本站不进行额外附加服务,虚拟产品一经售出概不退款(未进行购买下载可退充值款),文档一经付费(服务费)、不意味着购买了该文档的版权,仅供个人/单位学习、研究之用,不得用于商业用途,未经授权,严禁复制、发行、汇编、翻译或者网络传播等,侵权必究。
4、如你看到网页展示的文档有www.zixin.com.cn水印,是因预览和防盗链等技术需要对页面进行转换压缩成图而已,我们并不对上传的文档进行任何编辑或修改,文档下载后都不会有水印标识(原文档上传前个别存留的除外),下载后原文更清晰;试题试卷类文档,如果标题没有明确说明有答案则都视为没有答案,请知晓;PPT和DOC文档可被视为“模板”,允许上传人保留章节、目录结构的情况下删减部份的内容;PDF文档不管是原文档转换或图片扫描而得,本站不作要求视为允许,下载前自行私信或留言给上传者【自信****多点】。
5、本文档所展示的图片、画像、字体、音乐的版权可能需版权方额外授权,请谨慎使用;网站提供的党政主题相关内容(国旗、国徽、党徽--等)目的在于配合国家政策宣传,仅限个人学习分享使用,禁止用于任何广告和商用目的。
6、文档遇到问题,请及时私信或留言给本站上传会员【自信****多点】,需本站解决可联系【 微信客服】、【 QQ客服】,若有其他问题请点击或扫码反馈【 服务填表】;文档侵犯商业秘密、侵犯著作权、侵犯人身权等,请点击“【 版权申诉】”(推荐),意见反馈和侵权处理邮箱:1219186828@qq.com;也可以拔打客服电话:4008-655-100;投诉/维权电话:4009-655-100。