1、Ferroptosis is a form of necrotic cell death marked by the oxidative modification of phospholipid membranes via an iron-dependent mechanism1.An initial characterization of this pathway demonstrated that cysteine depletion,which leads to the exhaustion of the intracellular pool of glutathione(reduced
2、)(GSH)specifically triggers this form of cell death2.The requirement for GSH to protect from ferroptosis was later related to the optimal activity of the enzyme glutathione peroxidase 4(GPX4),a selenoprotein required for the efficient reduction of peroxidized phospholipids35 and to suppress the acti
3、vation of arachidonic acid(AA)-metabolizing enzymes6,which may contribute to the process of phospholipid peroxidation.Since then,a complex interplay between lipid,iron and cysteine metabolism has emerged as an important regulator of this cell death pathway.have also put forward the importance of tra
4、nsferrin trafficking and ferritin degradation through the process of ferritinophagy,a specific form of autophagy required for the degradation of ferritin,as critical determinants of ferroptosis sensitivity via an increase in the so-called labile iron pool1518.Despite the general importance of this p
5、athway to sustaining cell survival in non-cancerous cells and tissues19,it has been demonstrated that several oncogenic pathways render cancer cells extremely susceptible to this form of cell death through the modulation of key regulatory ferroptosis checkpoints2024.The recognition that oncogenic si
6、gnalling generates an inherent ferroptosis sensitivity puts forward a curious dilemma:how can the downregulation of mechanisms that suppress ferroptosis,associated with an increase in the steady-state levels of lipid peroxidation,provide a growth or survival advantage to cancer cells?Spurred by this
7、 apparent paradox,in this Opinion article,we present a discussion of the recent advances in the understanding of ferroptotic processes and offer a perspective on how the modulation of key elements regulating ferroptosis sensitivity could ultimately impinge on the interactions of cancer cells with th
8、e immune compartment.We provide a GPX4-centric view of how the modulation of key metabolic determinants that ultimately impact on the activity of this critical pro-survival protein controls relevant events required for cancer growth and persistence.We also discuss the related discovery of the involv
9、ement of AA metabolism in immune evasion and propose that AA-derived oxidation products generated during ferroptosis or by ferroptosis-sensitive cells could lead to a similar outcome.We believe this knowledge should guide us in assessing the benefits and potential pitfalls of triggering ferroptosis
10、in the context of cancer treatment.Regulation of ferroptosis by GPX4GPXs are a family of enzymes that reduce hydroperoxides at the expense of the oxidation of two molecules of GSH.The optimal activity of these enzymes is thus directly linked to GSH metabolism,whereby a decrease in cysteineGSH metabo
11、lism ultimately suppresses In the majority of cells in culture,sensitivity to ferroptosis is dictated by the presence of acyl-CoA synthetase long chain family member 4(ACSL4),an enzyme responsible for the esterification of polyunsaturated fatty acids(PUFAs)to acyl-CoA,a required step for the formati
12、on of PUFA-containing phospholipids79.How exactly oxidation of PUFAs above a certain threshold drives cell death is,however,currently unknown:it might be caused by the rupture of the plasma membrane in response to the accumulation of truncated phospholipid species or potentially by the inactivation
13、of critical pro-survival proteins by lipid-derived electrophiles originating from lipid peroxidation10,11.Additionally,cystine supply through the activity of the cystineglutamate antiporter(system xc-)or the transsulfuration pathway has been recognized as a critical upstream process of ferroptosis12
14、14(Fig.1).Further studies OPINIONFerroptosis at the crossroads of cancer-acquired drug resistance and immune evasionJosPedroFriedmann Angeli ,DmitriV.Krysko and MarcusConrad Abstract|Ferroptosis is a recently recognized cell death modality that is morphologically,biochemically and genetically distin
15、ct from other forms of cell death and that has emerged to play an important role in cancer biology.Recent discoveries have highlighted the metabolic plasticity of cancer cells and have provided intriguing insights into how metabolic rewiring is a critical event for the persistence,dedifferentiation
16、and expansion of cancer cells.In some cases,this metabolic reprogramming has been linked to an acquired sensitivity to ferroptosis,thus opening up new opportunities to treat therapy-insensitive tumours.However,it is not yet clear what metabolic determinants are critical for therapeutic resis tance a
17、nd evasion of immune surveillance.Therefore,a better understanding of the processes that regulate ferroptosis sensitivity should ultimately aid in the discovery of novel therapeutic strategies to improve cancer treatment.In this Perspectives article,we provide an overview of the known mechanisms tha
18、t regulate sensitivity to ferroptosis in cancer cells and how the modulation of metabolic pathways controlling ferroptosis might reshape the tumour niche,leading to an immunosuppressive microenvironment that promotes tumour growth and progression.volume 19|JulY 2019|405PERSPECTIvESNATuRe RevIewS|Can
19、CerGPX activity.The GPX family consists of eight distinct members in mammals.GPX1,GPX2,GPX3 and GPX4 are selenoproteins harbouring a selenocysteine(Sec)in their catalytic centres,and GPX6 is a selenoprotein only in humans,whereas all others use a peroxidatic cysteine in their active site25.All GPXs
20、work as dedicated enzymes responsible for the detoxification of H2O2 and organic peroxides.Unlike other GPXs,GPX4 has a broader substrate preference,being the only enzyme so far described able to directly reduce complex phospholipid hydroperoxides26.This unique activity of GPX4 is likely why it is t
21、he sole GPX essential for embryogenesis27.It has also been recently demonstrated that several cancer states driven by oncogenic mutations and through stem cell-like or dedifferentiated states converge on an exquisite metabolic state addicted to GPX4 activity28.Thereby,proper functioning of GPX4 appe
22、ars to be critical for cell survival,as it is responsible for the efficient removal of phospholipid hydroperoxides.Phospholipid hydroperoxides,if not efficiently quenched by GPX4,are able to trigger a catalytic reaction in the presence of transition metals such as iron that eventually causes cell de
23、ath29.GPX4 has also been proposed to contribute to other cell death modalities,and some(early)reports have linked GPX4 activity to sensitivity to apoptosis30,necroptosis31 and pyroptosis32.Yet it remains unclear whether these cell death pathways indeed share common features33 or whether the occurren
24、ce of lipid hydroperoxides just sensitizes to cell death stimuli.Hence,it remains puzzling why certain oncogenic signalling allows cancer cells to exist in such a vulnerable state.Or perhaps there are still yet to be discovered benefits arising from such an acquired vulnerability for tumour persiste
25、nce.Ferroptosis regulation in cancerMechanisms underlying susceptibility and resistance to ferroptosis particularly in the context of cancer have been an intense area of research in the past few years.Although it is well accepted that ferroptosis execution requires the oxidation of PUFAs,the underly
26、ing mechanisms of how oncogenic mutations and other non-oncogenic cancer-relevant states sensitize to ferroptosis have started to emerge but remain largely uncharacterized.In accordance with this concept,several potential mechanisms to target this vulnerable state have been put forward and are brief
27、ly discussed in Box1.Tumour suppressors control ferroptosis sensitivity.The tumour suppressor p53,also referred to as the guardian of the genome,which is mutated in approximately 50%of all cancers34,was the first to be linked to increased sensitivity to ferroptosis.Initial associations between p53 a
28、nd ferroptosis came from studies using a mouse model in which three lysines(K117R,K161R and K162R)in the p53 DNA binding site are simultaneously mutated(p53-3KR mice).Cells in p53-3KR mice,while not able to undergo apoptosis or cell cycle arrest,are still resistant to spontaneous tumorigenesis by a
29、mechanism that requires metabolic adaptation35.Further characterization of these animals demonstrated that the metabolic alteration required to suppress tumorigenesis was the inhibition of transcription of Slc7a11,which encodes the substrate-specific subunit of system xc-22(Fig.1).Repression of SLC7
30、A11 was sufficient to sensitize cancer cells to an oxidant insult,rendering cells prone to undergo a ferroptosis-like cell death.Moreover,the same group identified a fourth acetylation site(K98)in p53,which,when concomitantly mutated with the other previously described acetylation sites,generated a
31、p53 variant that was no longer able to bind to the promoter of Slc7a11.Unlike the p53-3KR mice,these mice developed tumours like those in p53 null mice36.This study thus draws a link between the antitumorigenic function of p53 and ferroptosis through the specific binding of p53 to the promoter of Sl
32、c7a11.Subsequently,another group has demonstrated that a common single nucleotide polymorphism found in p53 in individuals of African descent,which yields the mutant form P47S,is associated with an increased incidence of cancer in mouse models,and cells carrying this mutation are resistant to ferrop
33、tosis via altered glutamine metabolism37.If indeed increased sensitivity to ferroptosis is a major contributor to tumour suppression by p53,an additional question arises:what would be the physiologically relevant stressor that ultimately sparks the ferroptosis cascade?For now,it can be speculated th
34、at potential candidates could be H2O2 generated by natural killer(NK)cells through NADPH oxidase 2(NOX2)38.Another potential critical function of p53 in regulating ferroptosis might be based on its recent recognition as a key mediator of the mevalonate pathway.Under metabolic stress,p53 mediates the
35、 expression of ATP-binding cassette subfamily A member 1(ABCA1).ABCA1 is then responsible for the retrotranslocation of cholesterol from the plasma membrane to the endoplasmic reticulum,leading to the inactivation of sterol regulatory element binding protein 2 (SREBP2)39.Inhibition of SREBP2 causes
36、an overall suppression of transcription of genes in the mevalonate pathway,ultimately suppressing the production of several metabolites,such as squalene and Glossary-OxidationA catabolic process in which fatty acid molecules are oxidized in mitochondria to generate acetyl-CoA,NADH and FADH,the last
37、two of which drive forces of the electron transport chain.Conventional type 1 dendritic cell(cDC1).A subset of dendritic cells dependent on the transcription factor BATF3 for development and characterized by the specific expression of C-type lectin receptor DNgR1.EicosanoidsBioactive metabolites der
38、ived from the enzymatic and non-enzymatic oxidation of arachidonic acid and other polyunsaturated fatty acids that are 20 carbon units in length.Labile iron poolA transient pool of chelatable redox-active iron.Mevalonate pathwayA metabolic pathway responsible for the generation of sterol isoprenoids
39、,such as cholesterol,and non-sterol isoprenoids including dolichol,haem A,isopentenyl tRNA and ubiquinone.Necrotic cell deathin contrast to the prototype of programmed cell death,that is,apoptosis,this umbrella term is used to identify cells that share similar terminal features that include,but are
40、not limited to,extracellular extravasation and immunogenicity.Peroxidatic cysteineA cysteine residue found in the catalytic site of several redoxins that is responsible for the nucleophilic attack of a peroxide bond.Transsulfuration pathwayA metabolic pathway responsible for the interconversion of m
41、ethionine to cysteine.406|JulY 2019|volume 19 volume 19|JulY 2019|407NATuRe RevIewS|CanCerPersPectivesFPN1Fe3+Fe2+TFRCTransferrinEndosomaluptakeTranssulfurationpathwayMevalonatepathway Haemin FerritinFerritinophagyNCOA4NOX1DPP4LPCATDGATACSLATGLACSL4GLS2GLSGSRLOXp53p53ABCA1SREBP2HMGCRBAP1GPX4HIFSyste
42、m xc-Glutamine transporterCPTCystineGlutamateGlutamineGlutamineGlutamineGlutamineAcetyl-CoACystineGSHGSSGNADP+NADPH NADH FADH2CysteineHMG-CoAAA-CoAPEAAPSFAFAFA-CoAIsopentenyl-PPFarnesyl-PPOXPHOSLipolysis-oxidationCholesterolCoQ10PrenylatedproteinsGlutamateGlutamateLabile iron poolPE-OHPE-AA-OOHPE-AA
43、TCAcycleOGDH-KGERPLIN2HILPDALipid dropletMitochondrionFerroptosisSqualeneGSH biosynthesisFig.1|The main metabolic processes regulating ferroptosis and GPX4 activity.The key ferroptosis regulator glutathione peroxidase 4(GPX4)and upstream events modulating sensitivity are shown.Cysteine and glu-tathi
44、one(reduced)(GSH)availability supported by cystine uptake or the transsulfuration pathway is at the core of ferroptosis by providing reduc-ing equivalents for the optimal function of GPX4(ReFs3,4).This has been recently recognized as an important checkpoint controlled by the known tumour suppressors
45、 BRCA1-associated protein 1(BAP1)47 and p53(ReF.22),generating an intrinsic sensitivity to ferroptosis.The mevalonate pathway is involved in ferroptosis by generating a series of biomolecules with potential anti-ferroptotic activity such as squalene41,ubiquinone40 and isopentenyl-pyrophosphate(PP)21
46、,the last of which stabilizes the selenocysteine-specific tRNA required for efficient GPX4 translation.Iron uptake via the transferrin receptor or degradation of ferritin16,17 iron stores increases the labile iron pool,thereby sensitizing cells to ferropto-sis via facilitation of a Fenton-like react
47、ion of pre-formed lipid hydroper-oxides.Iron uptake and processing,acyl-CoA synthetase long chain family member 4(ACSL4)-dependent shaping of the cellular phospholip-idome7 and the tricarboxylic acid(TCA)cycle are additional cellular pro-cesses that may contribute to ferroptosis sensitization.Recent
48、ly,the impact of the hypoxia-inducible factor(HIF)system on fatty acid(FA)metabolism has been appreciated20,and the mobilization of lipid from droplets leads to modulation of ferroptosis sensitivity,depending on the FA composition of the latter.Additionally,channelling of polyunsaturated fatty acids
49、(PUFAs)for catabolic purposes lowers their incorporation into phospholipids,thus decreasing sensitivity to ferroptosis6,20.-KG,-ketoglutarate;AA,arachidonic acid;ABCA1,ATP-binding cassette sub-family A member 1;ATGL,adipose triglyceride lipase(also known as PNPL A2);CoQ10,coenzyme Q10;CPT,carnitine
50、palmitoyltransferase;DGAT,diacylglycerol O-acyltransferase;DPP4,dipeptidyl peptidase 4;ER,endoplasmic reticulum;FPN1,ferroportin 1(also known as SLC40A1);GLS,glutaminase;GSR,glutathione disulfide reductase;GSSG,glutathione disulfide;HILPDA,hypoxia-inducible lipid droplet-associated;HMGCR,HMG-CoA red