1、REVIEW ARTICLEOPENPyroptosis:mechanisms and diseasesPian Yu1,2,3,4,5,Xu Zhang1,2,3,4,5,Nian Liu1,2,3,4,5,Ling Tang1,2,3,4,5,Cong Peng1,2,3,4,5and Xiang Chen1,2,3,4,5Currently,pyroptosis has received more and more attention because of its association with innate immunity and disease.Theresearch scope
2、 of pyroptosis has expanded with the discovery of the gasdermin family.A great deal of evidence shows thatpyroptosis can affect the development of tumors.The relationship between pyroptosis and tumors is diverse in different tissues andgenetic backgrounds.In this review,we provide basic knowledge of
3、 pyroptosis,explain the relationship between pyroptosis andtumors,and focus on the significance of pyroptosis in tumor treatment.In addition,we further summarize the possibility ofpyroptosis as a potential tumor treatment strategy and describe the side effects of radiotherapy and chemotherapy caused
4、 bypyroptosis.In brief,pyroptosis is a double-edged sword for tumors.The rational use of this dual effect will help us further explorethe formation and development of tumors,and provide ideas for patients to develop new drugs based on pyroptosis.Signal Transduction and Targeted Therapy (2021)6:128;h
5、ttps:/doi.org/10.1038/s41392-021-00507-5INTRODUCTIONThe earliest research on pyroptosis can be traced back to 1986.Friedlander pointed out in the report that treatment of primarymouse macrophages with anthrax lethal toxin(LT)resulted in celldeath and rapid release of cell contents.1Cerretti et al.an
6、dThornberry et al.observed that ICE(interleukin-1-convertingenzyme,caspase-1),discovered for the first time in 1989,2was aninflammatory caspase,processing precursor IL-1 into matureIL-1.3,4In 1992,Zychlinsky et al.discovered pyroptosis for the firsttime,and they found suicide in the Gram-negative ba
7、cterialpathogen Shigella flexneri-infected macrophages.5In 1996,Chenet al.reported that invasion plasmid antigen B(ipaB)of Shigellaflexneri could bind directly to ICE and caused the enzyme to beactivated in infected macrophages.6This form of cell deathwas originally deemed to be apoptosis because so
8、me of itscharacteristics were similar to apoptosis,such as caspase-dependent,DNA damage,and nuclear condensation.Afterward,this form of death was observed to be different from apoptosis.In2001,DSouza et al.pointed out the term of pyroptosis,whichcomes from the Greek roots pyro(fire/fever)and ptosis(
9、to-sis,falling),to describe pro-inflammatory programmed cell death.7This is the first definition of pyroptosis,which makes thedistinctionbetweenpyroptosisandapoptosis(anon-inflammatory program of cell death).7In 2002,Inflammasomewas first considered to activate inflammatory caspases andprocess pro-I
10、L-1.8Afterward,Petr et al.found non-canonicalcaspase-11 could induce cell death without relying on caspase-1when the host was infected with Salmonella.9Pyroptosis wasconsidered to be caspase-1-induced monocyte death for a longtime,.10,11Later,it was reported that caspase-1 or caspase-11/4/5was activ
11、ated during this process,and gasdermin D(GSDMD)wascleaved,and the N-terminal domain can oligomerize to form poresin thecellmembrane,inducing cellmembrane rupture.12Interestingly,reports in recent years have shown that GSDMD-mediated pyroptosis can be blocked by some factors.Caspase-3/7cleaved GSDMD
12、at Asp87 site,causing inactivation of thepyroptotic activity of GSDMD.13In addition,the endosomalsorting complexes required for transport(ESCRT)machinery couldeliminate GSDMD pores from the plasma membrane,resulting inthe inhibition of GSDMD-mediated pyroptotic cell death andlimite the release of IL
13、-1 after the activation of inflammasome.14Humphries et al.found that the intermediate product oftricarboxylic acid cycle,fumarate,also dampened pyroptosis.15Both fumarate and dimethyl fumarate(DMF)could preventGSDMD from being processed and activated by caspases bysuccinizing the cysteine of GSDMD.1
14、5In 2017,Wang et al.andRogers et al.showed that chemotherapeutic agents can alsoinduce pyroptosis by activating caspase-3 to shear GSDME.16,17Subsequently,caspase-8 was indicated to cause pyroptosis andaffect inflammasome function.18In 2020,it was reported thatgranzyme B(GzmB)can directly cleave GSD
15、ME and activatepyroptosis,further activating the antitumor immune response andinhibiting tumor growth.19In the same year,granzyme A(GzmA)in cytotoxic lymphocytes was found to enter target cells throughperforin and induce pyroptosis by hydrolyzing GSDMB at theLys229/Lys244 site,which renewed our unde
16、rstanding of pyr-optosis.20More recently,pyroptosis has made further progress.Hou et al.found that under hypoxia,activated p-Stat3 promotednuclear PD-L1 translocation.Nuclear PD-L1 and p-Stat3 synergis-tically promote the expression of GSDMC,and caspase-8 activatedby TNF-derived from macrophages can
17、 cleave GSDMC intoN-GSDMC at the D365 site,resulting in pyroptosis ultimately21(Fig.1).Tumors use multiple strategies to avoid or limit the cell deathpathway.22In some cases,tumors can be killed by different ways,such as apoptosis,necrosis,autophagy and pyroptosis.23,24Received:23 August 2020 Revise
18、d:14 January 2021 Accepted:20 January 20211The Department of Dermatology,Xiangya Hospital,Central South University,Changsha,Hunan,China;2National Clinical Research Center for Geriatric Disorders,XiangyaHospital,Changsha,Hunan,China;3Hunan Key Laboratory of Skin Cancer and Psoriasis,Xiangya Hospital,
19、Changsha,Hunan,China;4Hunan Engineering Research Center of SkinHealth and Disease,Xiangya Hospital,Changsha,Hunan,China and5Xiangya Clinical Research Center for Cancer Immunotherapy,Central South University,Changsha,Hunan,ChinaCorrespondence:Cong Peng()or Xiang Chen() Transduction and Targeted Thera
20、py The Author(s)20211234567890();,:Apoptosis and other modes of death are important anticancerdefense mechanisms that have been widely studied,but therelationship between pyroptosis and cancer is not fully under-stood at present.Pyroptosis is closely related to nervous systemdiseases,infectious dise
21、ases,autoimmune diseases,cardiovasculardiseases,and tumors.2528With further research,the relationshipbetween pyroptosis and tumors is becoming increasingly clear,which provides some strategies for clinical treatments.We focus on the mechanism,the diverse functions in varioustumors and the potential
22、clinical value of pyroptosis.Thesefindings have raised awareness of tumors and identified a numberof potential cancer treatments.We look forward to communicat-ing the recent achievements in pyroptosis research and itsdevelopment in the field of oncology.These findings improvethe understanding of tum
23、ors and identify a number of potentialtumor treatments.GASDERMIN,THE EXECUTIONER OF PYROPTOSISPyroptosis was defined as gasdermin-mediated programmeddeath in 2015.29The gasdermin superfamily is composed ofgasdermin A/B/C/D(GSDMA/B/C/D),gasdermin E(GSDME,alsoreferred to as DFNA5)and DFNB59(Pejvakin,P
24、JVK)in human(Gsdma1-3,Gsdmc1-4,Gsdmd,Dfna5,and Dfnb59 in mice).3034Among these conserved proteins,GSDMD and DFNA5 are mostdeeply studied in pyroptotic death.Except for Pejvakin,all thesemembers consist of two conserved domains,the N-terminal pore-forming domain and the C-terminal repressor domain(PF
25、D andRD).3538The PFD of most gasdermins could induce pyroptosis,which has not yet been detected for Pejvakin.17,30,39In general,gasdermins maintain oligomerization through the interactionbetween PFD and RD,and the cytotoxic effects of PFD could beinhibited by RD.37,38When the host is stimulated by a
26、 variety ofexogenous or endogenous factors,gasdermins are cleaved bysomecaspasesorgranzymes,andtheN-terminalPFDisdissociated from the C-terminal RD,and then the N-terminalPFD oligomerizes and forms pores in the cell membrane,causingthe release of inflammatory molecules and cell pyroptoticdeath.30,40
27、,41Although a number of gasdermin family proteinshave been reported to be linked to human diseases,20,29,39,4263the specific mechanism and function remain to be studied.THE CHARACTERISTICS OF PYROPTOSISPyroptosis is composed of“pyro”and“ptosis”.“Pyro”means fire,indicating the properties of inflammat
28、ion of pyroptosis,but“ptosis”means falling,which is consistent with other forms ofprogrammed cell death.7There are some similarities betweenpyroptosis and apoptosis,such as DNA damage and chromatincondensation.64,65Interestingly,pyroptotic cells emerged swellingand a lot of bubble-like protrusions a
29、ppear on the surface of thecellular membrane before its rupture.66Similarly,membraneblebbing also occurs during apoptosis,and caspase-3 is necessaryfor this process.6776However,the unique morphological char-acteristics of pyroptosis are obviously different from those ofapoptosis.It is generally beli
30、eved that apoptosis is a safe form ofdeath,but pyroptosis can cause inflammation,activated byextracellular or intracellular stimulation,such as bacterial,viral,toxin,and chemotherapy drugs.77In fact,unlike the explosiverupture associated with necrosis,pyroptosis causes flattening ofthe cytoplasm due
31、 to plasma membrane leakage.66In addition,caspases activation or release of granzymes results in the N-terminal of gasdermin oligomerizationand poreformation(12m in diameter)in the plasma membrane,which allowsmature IL-1/IL-18 with a diameter of 4.5nm and caspase-1 with adiameter of 7.5nm to pass th
32、rough,respectively.30In themeantime,the water entering through the pores causes cellswelling and osmotic lysis,thus resulting in rupture of the plasmamembrane and the release of IL-1 and IL-18.78,79Thus,thepyroptotic cells are permeable to 7-aminoactinomycin(7-AAD),propidium iodide(PI),and ethidium
33、bromide(EtBr)because of thelow molecular weight of these dyes.79On the contrary,incomparisonwithpyroptoticcells,apoptoticcellsmaintainmembrane integrity,80so that these dyes cant stain them.8184Intriguingly,similar to apoptotic cells,Annexin V also stainspyroptotic cells and the dye binds to phospha
34、tidyl serine(PS).85Therefore,Annexin V cannot differentiate apoptotic cells frompyroptotic cells.In addition,apoptotic bodies are formed in theprocess of apoptosis,while pyroptotic bodies are formed in theprocess of pyroptosis.80Interestingly,the diameter of pyroptoticbodies is similar to that of ap
35、optotic bodies,and thier size are both15m.66Besides,there is a very special form of DNA damage with dUTPnick-end labeling(TUNEL)staining positive in the early stage ofpyroptosis,79,8693which is different from that of apoptosis.Compared with apoptosis,the intensity of DNA damage is lowerin pyroptotic
36、 cells.The DNA fragmentation of pyroptosis israndom and the nucleus remains intact,9497while the apoptoticDNA fragment is ordered and the nucleus is fragmented.23,98100Interestingly,caspase activation is associated with both pyroptosisand apoptosis.Initially,pyroptosis was considered to be caspase-1
37、-related cell death.5,23,101,102It is worth mentioning that recentFig.1The timeline of pyroptosisPyroptosis:mechanisms and diseasesYu et al.2Signal Transduction and Targeted Therapy (2021)6:128 studies have shown that other caspases,including caspase-3/4/5/6/8/9/11,alsocausepyroptosisinotherdifferen
38、tcells,16,17,29,39,94,103105and play major roles in innate immunityand tumorigenesis.106111Caspase-3 was previously thought to bethe executor of apoptosis,but it was suggested that caspase-3 canalso induce pyroptosis by cleaving GSDME.16,17,71More surpris-ingly,the apoptosis-related protein caspase-
39、8 can also directlycleave GSDMD to induce pyroptosis.103In addition,the activationof caspase-9 is also involved in pyroptosis by cleaving andactivating caspase-3,112and caspase-6 mediates the cleavage ofGSDMC.21Although current studies have found that caspase-1andcaspase-4/5/11areonlyassociatedwithp
40、yroptosis,while caspase-2,caspase-7,and caspase-10 are only related toapoptosis,36,113117theconnectionsbetweencaspasesandpyroptosis as well as caspases and apoptosis may be reportedone after another in the future with the deepening of studies.Apoptosis is affected by the level of ATP,and apoptosis i
41、saccompanied by the activation of PARP,causing ATP depletion.118However,the effector proteins of pyroptosis belong to thegasdermin family23(Tables 1 and 2).MOLECULAR MECHANISM OF PYROPTOSISCanonical pathwayCanonicalpyroptoticdeathismediatedbyinflammasomeassembly,which is accompanied by GSDMD cleavag
42、e and IL-1and IL-18 release.10,119128Inflammasomes are multimolecularcomplexes that are activated when the host is resistant tomicrobial infection and also facilitate the development of adaptiveimmune responses.In addition,Inflammasomes are also asso-ciated with non-microbial diseases.There is consi
43、derable evidencethat inflammasomes and their related cytokines play crucial rolesin oncogenesis,such as proliferation,metastasis,and invasion.129137The assembly of inflammasome begins with cytosolic patternrecognitionreceptors(PRRs,alsoknownasinflammasomesensors),which are capable of recognizing pat
44、hogen-associatedmolecular patterns and danger-associated molecular patterns(PAMPs and DAMPs).138,139Activation of PRRs promotes down-stream signaling pathway and causes type I interferons generationand pro-inflammatory cytokines release.129,140144PRRs assemblewith pro-caspase-1 and ASC to form infla
45、mmasomes afterstimulation of cells by signal molecules such as bacteria andviruses.11,141,145152At present,the inflammasome sensors NLRP1,NLRP3,NLRC4,AIM2,and pyrin are able to assemble canonical inflammasomesand have been relatively well studied.Most inflammasomesare constituted by three components
46、:(i)leucine-rich repeatcontaining proteins(NOD-like receptors,NLRs),(ii)the adapterapoptosis-associated speck-like protein containing a caspaserecruitment domain(CARD)(ASC),and(iii)pro-caspase-1.NLRsusually consist of a leucine-rich repeat(LRR),a nucleotide-bindingoligomerization domain(NACHT),and a
47、 CARD or pyrin domain(PYD),153156divided into NLRPs or NLRCs according to whethertheir N terminal contain PYD or CARD.The NLRCs have one ormore CARD at their N terminal such as NLRC4,but the NLRPscontain PYD such as NLRP1 and NLRP3.101,143,157Compared withNLRP3,NLRP1 contains extra function-to-find
48、domain(FIIND)andCARD domains at the N terminal.158Human NLRP1 carry threeparalogues in mice:NLRP1a/b/c,and these NLRP1 in mice lackPYD.159NLRP1b has been studied relatively extensively andresponds to the Toxoplasma gondii,Val-boro-Pro,and the Bacillusanthracis anthrax lethal toxin.160163NLRP3 senses
49、 a variety ofstimulus,such as toxins,pathogens,metabolites,crystallinesubstances,nucleic acids,and ATP.164The initial recognition ofligands by various NAIP proteins is necessary for NLRC4 inflamma-some activation.The human NAIP can directly bind to the flagellinand proteins of the type 3 secretion s
50、ystem(T3SS).165168In contrastto human NAIP,the mouse NAIP1,NAIP2,NAIP5,and NAIP6recognize the needle of T3SS,the inner rod of the T3SS,flagellin,and flagellin,respectively.165,166,169Then,NAIPs induce the recruit-ment and oligomerization of NLRC4 to form the NLRC4 inflamma-somecomplex,leadingtothecl