Pyroptosis in Cancer_ Friend or Foe_.pdf

cancersReviewPyroptosis in Cancer:Friend or Foe?Xiuxia Lu,Tianhui Guoand Xing Zhang*?Citation:Lu,X.;Guo,T.;Zhang,X.Pyroptosis in Cancer:Friend orFoe?Cancers 2021,13,3620.https:/doi.org/10.3390/cancers13143620Academic Editor:Stephen J.BeebeReceived:11 June 2021Accepted:14 July 2021Published:20 July 2021Publishers Note:MDPI stays neutralwith regard to jurisdictional claims inpublished maps and institutional affil-iations.Copyright:2021 by the authors.Licensee MDPI,Basel,Switzerland.This article is an open access articledistributedunderthetermsandconditions of the Creative CommonsAttribution(CC BY)license(https:/creativecommons.org/licenses/by/4.0/).Melanoma and Sarcoma Medical Oncology Unit,State Key Laboratory of Oncology in South China,Collaborative Innovation Center for Cancer Medicine,Sun Yat-sen University Cancer Center,Guangzhou 510060,China;(X.L.);(T.G.)*Correspondence:Simple Summary:Pyroptosis is a new form of programmed cell death that differs from apoptosis interms of its release of inflammatory factors and its characteristic bubble-like morphology.Pyroptosiswas first discovered in the process of immune defense against bacterial infection,but the field ofresearch soon spread to other inflammatory diseases and cancer.As cancer constitutes a seriousrisk for public health,numerous studies investigating pyroptosis in cancer have been carried outduring these years.Tumorigenesis and new therapeutic treatments have been the focus of muchrecent research.This review discusses the role of pyroptosis in tumorigenesis and its influence ontumor immunity.Abstract:Pyroptosis is an inflammatory form of programmed cell death that is mediated by pore-forming proteins such as the gasdermin family(GSDMs),including GSDMA-E.Upon cleavage byactivated caspases or granzyme proteases,the N-terminal of GSDMs oligomerizes in membranes toform pores,resulting in pyroptosis.Though all the gasdermin proteins have been studied in cancer,the role of pyroptosis in cancer remains mysterious,with conflicting findings.Numerous studieshave shown that various stimuli,such as pathogen-associated molecular patterns(PAMPs),damage-associated molecular patterns(DAMPs),and chemotherapeutic drugs,could trigger pyroptosiswhen the cells express GSDMs.However,it is not clear whether pyroptosis in cancer induced bychemotherapeutic drugs or CAR T cell therapy is beneficial or harmful for anti-tumor immunity.Thisreview discusses the discovery of pyroptosis as well as its role in inflammatory diseases and cancer,with an emphasis on tumor immunity.Keywords:pyroptosis;gasdermin;inflammasome;cancer;immunity1.IntroductionProgrammed cell death mediated by specific signaling pathways plays a vital role inmorphogenesis,the maintenance of homeostasis,and various diseases 1.According tothe morphology changes involved,programmed cell death can be divided into lytic andnon-lytic cell death.Apoptosis is a well-studied form of non-lytic cell death without therelease of pro-inflammatory factors.However,pyroptosis and necroptosis are lytic andhighly inflammatory in nature 2,3.Cross talk between the various forms of cell death ismediated by numerous pathways.Among these,caspase 8 is considered as a molecularswitch that controls apoptosis,necroptosis,and pyroptosis 4,5.Pyroptosis was first studied in the field of immune defense against pathogens.Thisfield of research gradually extended to other diseases,especially cancer,as cancer hasbecome a leading heath menace in recent decades.Many studies have found that tumorcells can be killed through pyroptosis,but the role of pyroptosis in tumorigenesis or anti-tumor immunity has not yet been clearly summarized.In this review,we aim to discusshow pyroptosis was discovered and the roles of pyroptosis in human diseases,includingtumors,with an emphasis on the relationship between pyroptosis and tumor immunity.Cancers 2021,13,3620.https:/doi.org/10.3390/cancers13143620https:/ 2021,13,36202 of 142.The Discovery of PyroptosisPyroptosis was first observed in 1992 when A.Zychlinsky treated macrophages withShigella flexneri and saw lytic cell death 6.However,this was considered to be a caseof apoptosis at that time,and not until 2000 did Boise and Collins name it pyroptosis 7.Cookson 8 demonstrated that,unlike apoptosis,pyroptosis was associated with therelease of some proinflammatory factors and was dependent on caspase-1 instead ofcaspase-3,as in apoptosis.With the breakthrough in research on the inflammasome 9,pyroptosis was found to be induced upon the activation of caspase-1/4/5/11 and to occurin both macrophage and non-macrophage cells 1014.The underlying mechanism ofhow inflammatory caspases trigger pyroptosis remained unknown until Feng Shao 15discovered that one of the gasdermin proteins,GSDMD,is required for caspase-1-mediatedpyroptosis.When cells respond to an exogenous pathogen or endogenous damage,acanonical inflammasome is formed by the adaptor protein ASC and upstream sensorsNLRP1b/NLRP3/NLRC4/AIM2/Pyrin,which in turn activates the effector pro-caspase 1,leading to its self-cleavage.The activated caspase 1 then cleaves GSDMD and the inflamma-tory factors pro-IL-18 and IL-1.In the non-canonical inflammasome pathway,lipopolysac-charide(LPS)directly binds to and activates pro-caspase 4/5 or murine pro-caspase 11.Then,the activated caspases cleave GSDMD,contributing to the oligomerization of theN-terminal in membranes to form pores 1620,leading to lytic cell death and the releaseof inflammatory cytokines such as IL-18,IL1,and HMGB1 21.Later,it was discoveredthat the gasdermin family GSDMA/B/C/D/E could all be cleaved by activated caspasesand granzyme proteases,and the N-terminal oligomerizes in membranes to form pores 22,leading to pyroptosis(Figure 1).Figure 1.Different pathways to pyroptosis.(a)Canonical pyroptosis:PAMPs such as Gram-negativebacteria,viruses,toxins and DAMPs such as intracellular ROS,ATP,potassium,cadmium can activatethe inflammasomes and activated caspase 1 can cleave GSDMD and pro-IL-1/IL-18.Non-canonicalpyroptosis:Bacterial lipopolysaccharide(LPS)directly binds to and activates pro-caspase 4/5 ormurine pro-caspase 11,then the activated caspases cleave GSDMD.(b)Chemotherapeutic drugsor inhibitors can disrupt the mitochondrial membrane and the release of cytochrome c activatescaspase 9 and caspase 3 to cleave GSDME and trigger pyroptosis.Caspase 3 could also be activatedby caspase 8 when death receptors are stimulated.(c)Cytotoxic T lymphocytes(CTLs)and naturalkiller(NK)cells release perforin to deliver serine protease granzymes(Gzms)into target cells,andthen GzmA and GzmB can cleave GSDMB/E,which triggers pyroptosis.Cancers 2021,13,36203 of 143.The Role of Pyroptosis in Inflammatory DiseasesAlthoughpyroptosiswasfirstdiscoveredinShigellaflexneri-infectedmacrophages23,Salmonella,various other bacteria 24,and viruses soon demonstrated pyroptosis induc-ing capability in target cells besides macrophages.In addition to its role in inflammatorydiseases,pyroptosis also plays a vital part in other ailments.Diabetes is a major risk fac-tor underlying cardiovascular diseases.Studies have shown that NLRP3 is a mediator ofpyroptosis in cardiomyocytes,leading to diabetic cardiomyopathy 2527.Moreover,nico-tine 28,cholesterol crystals 29,oxLDL 30,and cadmium 31 can disrupt the coronaryarterial endothelial cells via pyroptosis,causing atherosclerosis.Additionally,pyroptosis invascular smooth muscle cells and monocytes/macrophages also accelerates the pathogene-sis of coronary atherosclerosis.Pyroptosis has also been reported in common neurologicaldisorders.Increased intracellular calcium,mitochondrial dysfunction,and other endoge-nous compounds can activate the NLRP3 inflammasome and trigger pyroptosis in microgliaand dopamine neurons,increasing the incidence of neuroinflammation and promoting theprogression of Parkinsons disease 32 and inflammatory demyelination during multiplesclerosis(MS)33.Taken together,cell death by pyroptosis has been found to be a common factor associ-ated with the progression of many inflammation-associated diseases.Numerous studieshave shown that it is possible to attenuate inflammation by blocking pyroptosis with in-hibitors targeting caspase-1/3/4/5/11 or the NLRP3 inflammasome.HIV infection inducesthe cell death of quiescent lymphoid CD4 T cells by caspase-1-mediated pyroptosis,andthose dying CD4 T cells release inflammatory signals that cause more cells to die 34.Thisindicates that caspase 1 inhibitors could be a new class of anti-AIDS therapeutic targets.4.The Roles of Pyroptosis in Cancer:Promoting or Inhibiting the Tumor?4.1.The Role of Inflammasomes in CancerInflammasomes are protein complexes that are assembled in response to pathogensor intercellular danger.The type of inflammasome involved depends on the sensor used.These sensors consist of pyrin,AIM2,and nucleotide-binding domain(NOD)-like receptors(NLRs)such as NLRP1,NLRP3,and NLRC4,among which NLRP3 has been the mostwidely studied 35.The NLRP3 inflammasome is involved in a variety of inflammation-associated diseases.In terms of tumors,the NLRP3 inflammasome could enhance theproliferation and migration of A549 lung cancer cells 36(Table 1),and an increased expres-sion of NLRP3 was positively correlated to tumor growth in oral squamous cell carcinoma(OSCC)37(Table 1).Another study showed that NLRP3 could promote epithelial tomesenchymal transition in colon cancer cells in an inflammasome-independent manner 38(Table 1).Moreover,the NLRP3 inflammasome is involved in chemoresistance in oral squa-mous cell carcinoma 39(Table 1)and insensitivity to radiotherapy in glioblastoma 40(Table 1).Various studies have confirmed that the NLRP3-mediated release of IL-18 4143or IL-14447 enhances the malignancy of lymphoma,gastric cancer,breast cancer,coloncancer,and glioblastoma via promoting the proliferation of cancer,immunosuppression,angiogenesis,and metastasis 48,49.Similarly,Zhai et al.studied the tumor-promotingrole of NLRP1 and reported that NLRP1 could augment the activation of inflammasomesand suppress apoptosis in metastatic melanoma 50.Cancers 2021,13,36204 of 14Table 1.Roles of the NLRP3 inflammasome in cancer.Tumor TypesSignificanceExperimental ModelsResultsRefs.Lung cancertumor promoterLC cell linesThe activation of NLRP3 increased thetumor proliferation and migration.36OSCCtumor promoterOSCC cell lines and tissueThe enhanced expression of NLRP3 wascorrelated with tumor growthand metastasis.37The upregulation of NLRP3 correlates withthe chemoresistance of 5-FU in OSCC.39Colon cancertumor promoterCRC cell linesThe NLRP3 level was increased duringEMT,which was independent ofinflammasome activation.38Gliomatumor promoterglioma cell linesNLRP3 inflammasome contributed to theradiotherapy resistance in a xenograftmouse glioblastoma model.40Liver cancertumor suppressorHCC tissueThe deficiency of the NLRP3 inflammasomewas related to higher pathological gradesand advanced clinical stages in HCC.51Colorectal cancertumor suppressorNlrp3/,Asc/andCaspase1/miceNLRP3 inflammasome protected mice fromcolitis-associated colorectal tumorigenesis.52macrophages surroundedCRC tissueThe NLRP3 inflammasome inhibited thegrowth of liver colon cancermetastatic tumor.53Abbreviations:LC,lung cancer;OSCC,oral squamous cell carcinoma;CRC,colorectal cancer;EMT,epithelial-mesenchymal transition;HCC,hepatocellular carcinoma.On the contrary,a number of studies have also shown the anti-tumor activity of inflam-masomes.Lower levels of NLRP3 51(Table 1),NLRP1 54,and AIM2 55 proteins werefound in hepatocellular carcinoma(HCC),colorectal cancer(CRC),and gastric cancer(GC)compared to the adjacent normal tissue.A low level of these proteins was correlated withthe advanced stage and poor prognosis of HCC,suggesting that the inflammasomes servedas negative regulators in HCC tumorigenesis.The anti-tumor role of inflammasomes hasbeen extensively studied in colitis-associated cancer,showing that the secretion of IL-18mediated by the NLRP3 inflammasome could protect enterocytes from early-stage colitisinduced by dextran sulfate sodium(DSS)or azoxymethane(AOM)52,5658(Table 1).Fur-thermore,a study found that NLRC4 in tumor-associated macrophages(TAMs)inhibitedthe progression of melanoma independently of inflammasome activation 59.Additionally,the NLRP3 inflammasome in Kupffer cells suppressed colorectal cancer metastatic growthin the liver by promoting the maturation of NK cells and tumoricidal activity mediated byIL-18 53(Table 1).Overall,the role of the inflammasome in different cancer types is ambiguous(Figure 2).4.2.The Role of Gasdermin Family Proteins in CancerGasdermin family proteins,which include GSDMA,GSDMB,GSDMC,GSDMD,andGSDME,had been studied in other fields but not in cancers.Only in the last few yearshave their roles in pyroptosis and cancer been studied.Cancers 2021,13,36205 of 14Figure 2.Diverse roles of the inflammasome in cancer.(a)NLRP3 mediates the proliferation and invasion of tumor cells.A higher expression of NLRP3 in tumor is associated with the clinical outcomes of patients.(b)The release of IL-18/IL-1from tumor cells induces tumor proliferation,immunosuppression,angiogenesis,and metastasis.However,IL-18from myeloid cells or enterocytes can activate cytolytic immune cells and inhibit the formation of tumors(colorectal cancer)via initiating tissue repair.(c)Others.Inflammasomes such as NLRC4 in tumor-associated macrophages(TAMs)can inhibittumor progression.4.2.1.GSDMA,GSDMB and GSDMCTo date,the roles of GSDMA/B/C in tumors have been described only vaguely,and very limited information is available about them.GSDMA is usually expressed inepithelial cells and its lineage GSDMA3 has been proposed to be involved in epidermaldifferentiation 60,TNF-induced apoptosis 61,skin inflammation,and hair loss 6264.Polymorphisms of GSDMB as well as GSDMA were found to be linked to the developmentof childhood asthma 6567.GSDMA is frequently silenced in gastric cancers 68,69,indicating that GSDMA might function as a regulator of tumor suppression.Interestingly,GSDMB could be considered as an oncogene because of its enhanced expression in gastriccancers,hepatic carcinomas,cervical tumors,and breast cancer 7072.Additionally,manystudies have also proposed that GSDMB possessed protumor functions such as migration,metastasis,and resistance to therapy in HER2 breast cancer 73,74.Due to its constricted expression,there are no known diseases associated with GSDMC.GSDMC has been reported to be upregulated by transforming growth factor beta receptor2(TGFBR2)mutation in colorectal cancer(CRC),promoting tumor cell proliferation 75.Likewise,the overexpression of GSDMC was confirmed in lung adenocarcinoma(LUAD)patients,acting as a promising predictive factor 76.A recent study demonstrated that,under hypoxia,nuclear PD-L1 was found to enhance the expression of GSDMC,and breastcancer patients with an increased expression of GSDMC had poorer outcomes,suggestingthat the chronic tumor necrosis induced