Gasdermin E and pyroptosis in cancer
Gasdermin E 和癌症焦亡
基本信息
- 批准号:10375415
- 负责人:
- 金额:$ 49.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-03 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AffectApoptosisApoptoticBackBrainC-terminalCASP3 geneCD8-Positive T-LymphocytesCancer cell lineCaspaseCell DeathCell LineCell SurvivalCell membraneCellsCellular StressCessation of lifeChemotherapy and/or radiationCochleaColorectalColorectal CancerCytotoxic T-LymphocytesDataDecitabineDrug TargetingDrug resistanceEffectivenessEpidermal Growth Factor ReceptorEpigenetic ProcessEtoposideFamily memberGenesGoalsGranzymeHumanImmuneImmunityImmunocompetentImmunotherapyIn VitroInfectionInflammation MediatorsInflammatoryInvertebratesKRAS2 geneKidneyKiller CellsKnock-outLarge IntestineLipid BindingLungLymphocyteMalignant NeoplasmsMediatingMelanoma CellMetastatic Neoplasm to Lymph NodesMethylationMitochondriaModelingMucous MembraneMusMutateMutationN-terminalNatural Killer CellsNormal tissue morphologyPeptide HydrolasesPhagocytosisPharmaceutical PreparationsPlacentaProtein FamilyRadiationResistanceRoleSmall IntestinesStimulusStomachSyndromeT-Cell DepletionTestingTherapeuticTransplantationTumor ImmunityTumor Suppressor ProteinsTumor-infiltrating immune cellsVDAC1 genebasecancer cellcancer invasivenesscancer vaccinationchemotherapycytokinecytotoxicdeafnessdrug sensitivityflexibilityimmune clearanceimmunogenicimprovedin vivoinhibitorinsightloss of function mutationlung cancer cellmalignant breast neoplasmmalignant stomach neoplasmmelanomaneoplastic celloverexpressionperforinrecruitresponsetreatment responsetumortumor growthtumorigenesis
项目摘要
Caspase-3 activation during apoptosis can trigger caspase-3 cleavage of gasdermin E (GSDME). The
gasdermins (GSDM) are a family of proteins, whose cleavage activates inflammatory death, called pyroptosis.
N-terminal GSDM fragments form pores in the cell membrane that cause rapid cell death in which the cell swells,
activates and releases inflammatory cytokines and other inflammatory mediators, and eventually bursts. GSDME
cleavage converts noninflammatory apoptotic death to more rapid inflammatory pyroptotic death. GSDME is not
expressed in most cancer cell lines, is epigenetically inactivated in gastric, colorectal and breast cancer, relative
to normal tissue, and mutated in some others. GSDME expression suppresses colony formation in gastric and
colorectal cancer and invasivity of breast cancer. Worse 5-year survival and an increase in lymph node
metastases are associated with reduced GSDME in breast cancer. Moreover, lack of GSDME promotes drug
resistance in melanoma and lung cancer cell lines. We hypothesize that GSDME acts like a tumor suppressor,
that some tumor cells avoid pyroptosis by downregulating or mutating GSDME and that the switch from
apoptosis to pyroptosis profoundly affects tumor cell survival, anti-tumor immunity and response to
chemotherapy and radiation. In preliminary data, cancer-associated GSDME mutations are shown to be
primarily loss of function mutations. Gsdme knockout in cancer lines promoted tumor growth while ectopic
GSDME expression strongly inhibited tumor growth in immune competent mice. The tumor suppressive role of
GSDME was lost in immunodeficient NOD.scid.Il2rg-/- (NSG) and Prf1-/- mice deficient in perforin and strongly
inhibited by NK or CD8 T cell depletion. GSMDE expression by the tumor increased infiltrating, functional CD8
T cells and NK cells. Based on these data, we hypothesize that GSDME suppresses tumor growth by
recruiting and activating anti-tumor killer lymphocytes. We also found that granzymes B and M, death-
inducing proteases of killer lymphocytes, directly cleave GSDME during killer cell attack to activate pyroptosis in
a caspase-independent manner, which is amplified by caspase activation. We also hypothesize that direct
granzyme cleavage of GSDME in cancer cells triggers pyroptosis and enhances their anti-tumor
immunity. Killer lymphocyte mediated death has previously been thought to be non-inflammatory. Our goal is
to test these hypotheses and develop mechanistic insights to understand whether and how suppression of
GSDME activation of pyroptosis in cancer cells impacts oncogenesis, drug sensitivity and protective immunity.
Our specific aims are to investigate the effect of GSDME mutation and expression on GSDME activation, lipid
binding, oligomerization and pore formation, on whether cell death by apoptotic stimuli or killer cells is
inflammatory and immunogenic, and whether and how GSDME affects tumor growth, immunity and responses
to therapy in vitro and in transplanted mouse tumor models.
凋亡过程中Caspase- 3的激活可触发Caspase- 3裂解气皮蛋白E (GSDME)。的
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Judy Lieberman其他文献
Judy Lieberman的其他文献
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