1、SpotlightFighting ResilientCancers with IronJonathan J.Chen1andLorenzo Galluzzi1,2,3,*Tumor progression and resistanceto treatment are often accompa-nied by the polarization of malig-nant cells towards a mesenchymalor poorly differentiated state.Sucha transition generates an accruedvulnerability to
2、the induction of fer-roptosis,potentiallypavingthewaytonoveltherapeuticstrategiesfor targeting residual disease inpatients with cancer.A large number of cell-intrinsic and cell-extrinsic mechanisms,including autoph-agy,cellular senescence,regulated celldeath(RCD),and immunosurveillance,is in place t
3、o prevent malignant transfor-mation or intercept neoplastic cell precur-sors as they form,hence mediatingrobust oncosuppressive functions 1,2.However,newly formed malignant cellscan occasionally escape these safe-guards and begin to proliferate as theyacquireconsistentphenotypic,meta-bolic,and immun
4、ological diversity andpolarizetowardsamesenchymalorpoorly differentiated state 3.Such anepithelial-to-mesenchymaltransition(EMT)not only enables the multistep pro-cess leading to the colonization of distantanatomical sites(the so-called meta-static cascade),but also endows malig-nant cells with an a
5、ccrued resistance to avariety of therapeutic regimens 4.Thus,tumor progression and acquired resis-tance to treatment,which are ultimatelyresponsibleformostcancer-relateddeaths,are intimately connected withthe reprogramming of malignant cellstowards a mesenchymal state(Figure 1).In line with this not
6、ion,the EMT hasattracted considerable attention as apotentially druggable process for cancertherapy4.Recentdatademonstratethatcancer cells existing in such a highlymesenchymal state exhibit an exquisitesensitivity to the inhibition of glutathioneperoxidase 4(GPX4)5,6,potentiallypaving the way to nov
7、el therapeuticstrategiesforovercomingresidualdisease in patients with cancer.GPX4isaselenocysteine-containingenzyme that catalyzes the glutathione-dependent reduction of specific lipidhydroperoxides into lipid alcohols 7.Byvirtue of this catalytic activity,GPX4robustlyinhibitsferroptosis,aniron-depe
8、ndent,lipid peroxide-driven form ofRCD that is involved in multiple patholog-ical settings,especially in the renal com-partment 2,8.Intriguingly,human breastcarcinoma BT474 cells experimentallydriven into acquired resistance to thetyrosine kinase inhibitor(TKI)lapatinib,but not parental BT474 cells,
9、displayedaccrued sensitivity to two distinct chemi-cal inhibitors of GPX4,namely,RSL3 andML210 5.Similar observations weremade for human melanoma A375 cells,lung adenocarcinoma PC9 cells,andovarian carcinoma Kuramochi cells uponacquisition of resistance to the BRAFinhibitor vemurafenib,the EGFR inhi
10、bitorerlotinib,or carboplatin plus paclitaxel,respectively.Moreover,the knockout ofGPX4fromchemoresistant,butnotparental,A375 cells was lethal,unless achemical inhibitor of ferroptosis,such asferrostatin-1(Fer-1),PD146176,or SCPI-2,was addedtotheculturemedium5.Inline with this finding,chemoresistant
11、TICB 1390 No.of Pages 2OncosuppressivemechanismsMicroenvironmentalselec?onConven?onaltreatmentFerroptosisinduc?onNewly formedcancer cellsLow-gradecancer cellsProgressingcancer cellsChemoresistantcancer cellsMesenchymalstateEpithelialstateEMTFigure 1.Non-Oncogene Addition to Glutathione Peroxidase 4(
12、GPX4)among Highly Mesench-ymal Cancer Cells Resistant to Chemotherapy.Newly formed cancer cells are efficiently eliminated bycell-intrinsic and cell-extrinsic oncosuppressive mechanisms.Occasionally,however,such mechanisms fail,allowing for the establishment of low-grade tumors.Microenvironmental fa
13、ctors and conventional chemother-apeutic regimens impose a strong selective pressure on progressing tumors,which is often accompanied bythe transition of malignant cells towards a highly mesenchymal or poorly differentiated state.In the case ofepithelial tumors,this process is referred to as epithel
14、ial-to-mesenchymal transition(EMT).Recent datasuggest that highly mesenchymal chemoresistant cancer cells exhibit an exquisite sensitivity to ferroptosisinduction via inhibition of GPX4.Trends in Cell Biology,Month Year,Vol.xx,No.yy1TICB 1390 No.of Pages 2BT474 cells had lower baseline levels ofredu
15、ced glutathione and NADPH com-pared with their parental counterparts,rendering them particularly prone to lipidperoxidation in response to RSL3.More-over,the survival of GPX4/44_TD$DIFF A375 cellsxenografted into immunodeficient miceand exposed to nonablative doses oftwo kinase inhibitors(dabrafenib
16、 and tra-metinib)dependedonthesystemicadministrationofFer-1.Conversely,parental A375 cells surviving nonablativechemotherapy in vivo recovered rapidproliferation upon Fer-1 withdrawal 5.Taken together,these findings suggestthat acquired chemoresistance is accom-paniedbyastateofnon-oncogeneaddic-tion
17、 to GPX4 that may be harnessed fortherapeutic purposes.Further corroborating this concept,a bio-informatic approach built on genetic sig-natures,proteomic data,and lineage-based correlation analysis identified aset of compounds with preferential cyto-toxicity for cancer cells in a highly mesen-chyma
18、lstatepreviouslylinkedtochemoresistance.Thesechemicalsincluded:(i)three GPX4 inhibitors(i.e.,RSL3,ML210,and ML162);(ii)ML239,which acts as an activator of fatty aciddesaturase 2(FADS2);and(iii)three sta-tins(i.e.,lovastatin,simvastatin,and flu-vastatin),all of which operate as inhibitorsof3-hydroxy-
19、3-methylglutaryl-CoAreductase(HMGCR)6.Publically avail-ablegenome-wideshort-hairpinRNA(shRNA)sensitivity data from 349 cancercellsunveiledastrikingcorrelationbetween susceptibility to GPX4 knock-down and sensitivity to RSL3 or ML210.Moreover,hierarchicalclusteringofapair-wise similarity matrix for 4
20、81 distinct com-pounds revealed a considerable proximitybetween statins and ferroptosis inducers.Indeed,statins were found to causeGPX4 downregulation as a consequenceof isopentenyl pyrophosphate depletion,defactoresemblingchemicalGPX4inhibitors in their mechanism of action6.Non-oncogene addiction t
21、o GPX4accompanied the highly mesenchymalstate linked to:(i)chemoresistance in cul-turedhumanlungadenocarcinomaHCC4006 cells;(ii)chemoresistance intwo different patient-derived pancreaticcell lines;(iii)neuroendocrine transitionin a panel of prostate cancer organoidsand benign cell lines;and(iv)chemo
22、re-sistance linked to transforming growthfactor beta 1(TGFB1)in patient-derivedmelanoma cell lines.These findings sug-gest that the EMT driven by chemother-apy or environmental factors,such asTGFB1,is often linked to an accrueddependency on GPX4 functions.Of note,zinc finger E-box binding homeobox 1
23、(ZEB1),but neither snail family transcrip-tional repressor 1(SNAI1;also known asSNAIL1)nor twist family bHLH transcrip-tion factor 1(TWIST1),was involved insuch a form of EMT,45_TD$DIFFpotentially linkedto the role of ZEB1 in lipid metabolism6.Finally,highly mesenchymal GPX4/cells,but not their epit
24、helial GPX4/counterparts,required systemic Fer-1availability to normally proliferate in vitroand to form tumors upon inoculation intoimmunodeficient animals 6.Cumula-tively,these results indicate that at leastsome forms of EMT engender a state ofnon-oncogene addition to GPX4.Thus,chemoresistance and
25、 the highlymesenchymalstatethatgenerallyaccom-panies it may 46_TD$DIFFrender tumors vulnerable toferroptosis-activatingagents.Unfortu-nately,thebioavailabilityofcurrentGPX4 inhibitors is incompatible with invivo applications 8.Of note,statin usewasindependentlyassociatedwithreduced mortality from 13
26、 distinct tumortypes in a retrospective study coveringthe entire Danish population diagnosedwith cancer between 1995 and 20079,and specifically with reduced recur-rence in cohorts of patients with breastcarcinoma 10.In view of the findingsdiscussed above,it is tempting to specu-late that(at least pa
27、rt of)such a beneficialeffect may stem from the control of che-moresistant cancer cells via GPX4 inhibi-tionandconsequentactivationofferroptosis(Figure 1).Further studiesare required to formally address this pos-sibility in preclinical andclinical settings.Inthe absence of bioavailable GPX4 inhib-it
28、ors,statins stand out as promising can-didates for the therapeutic induction offerroptosis in highly mesenchymal andchemoresistant cancer cells.AcknowledgmentsThe authors are supported by the Department ofRadiation Oncology of Weill Cornell Medical Collegeand by Sotio 47_TD$DIFFa.s.1Department of Ra
29、diation Oncology,Weill Cornell MedicalCollege,New York,NY,USA2Sandra and Edward Meyer Cancer Center,New York,NY,USA3Universit Paris Descartes/Paris V,Paris,France*Correspondence:deadocvodafone.it(L.Galluzzi).https:/doi.org/10.1016/j.tcb.2017.11.007References1.Kroemer,G.et al.(2015)Natural and therap
30、y-inducedimmunosurveillance in breast cancer.Nat.Med.21,112811382.Galluzzi,L.et al.Molecular mechanisms of cell death:recommendations ofthe Nomenclature Committee on CellDeath 2018.Cell Death Differ.(in press).3.Lamouille,S.et al.(2014)Molecular mechanisms of epi-thelial-mesenchymaltransition.Nat.Re
31、v.Mol.CellBiol.15,1781964.Marcucci,F.et al.(2016)Epithelial-mesenchymal transi-tion:a new target in anticancer drug discovery.Nat.Rev.Drug Discov.15,3113255.Hangauer,M.J.et al.(2017)Drug-tolerant persister cancercells are vulnerable to GPX4 inhibition.Nature 551,2472506.Viswanathan,V.S.et al.(2017)D
32、ependency of a therapy-resistant state of cancer cells on a lipid peroxidase path-way.Nature 547,4534577.Kagan,V.E.et al.(2017)Oxidized arachidonic and adrenicPEs navigate cells to ferroptosis.Nat.Chem.Biol.13,81908.Yang,W.S.et al.(2014)Regulation of ferroptotic cancercell death by GPX4.Cell 156,3173319.Nielsen,S.F.et al.(2012)Statin use and reduced cancer-related mortality.N.Engl.J.Med.367,1792180210.Ahern,T.P.et al.(2014)Statins and breast cancer prog-nosis:evidence and opportunities.Lancet Oncol.15,e461e4682Trends in Cell Biology,Month Year,Vol.xx,No.yy
