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Gasdermin E and pyroptosis in cancer

Gasdermin E 和癌症焦亡

基本信息

批准号：
10375415
负责人：
Judy Lieberman
金额：
$ 49.4万
依托单位：
BOSTON CHILDREN'S HOSPITAL
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：
https://reporter.nih.gov/project-details/10375415
关键词：
Affect Apoptosis Apoptotic Back Brain C-terminal CASP3 gene CD8-Positive T-Lymphocytes Cancer cell line Caspase Cell Death Cell Line Cell Survival Cell membrane Cells Cellular Stress Cessation of life Chemotherapy and/or radiation Cochlea Colorectal Colorectal Cancer Cytotoxic T-Lymphocytes Data Decitabine Drug Targeting Drug resistance Effectiveness Epidermal Growth Factor Receptor Epigenetic Process Etoposide Family member Genes Goals Granzyme Human Immune Immunity Immunocompetent Immunotherapy In Vitro Infection Inflammation Mediators Inflammatory Invertebrates KRAS2 gene Kidney Killer Cells Knock-out Large Intestine Lipid Binding Lung Lymphocyte Malignant Neoplasms Mediating Melanoma Cell Metastatic Neoplasm to Lymph Nodes Methylation Mitochondria Modeling Mucous Membrane Mus Mutate Mutation N-terminal Natural Killer Cells Normal tissue morphology Peptide Hydrolases Phagocytosis Pharmaceutical Preparations Placenta Protein Family Radiation Resistance Role Small Intestines Stimulus Stomach Syndrome T-Cell Depletion Testing Therapeutic Transplantation Tumor Immunity Tumor Suppressor Proteins Tumor-infiltrating immune cells VDAC1 gene base cancer cell cancer invasiveness cancer vaccination chemotherapy cytokine cytotoxic deafness drug sensitivity flexibility immune clearance immunogenic improved in vivo inhibitor insight loss of function mutation lung cancer cell malignant breast neoplasm malignant stomach neoplasm melanoma neoplastic cell overexpression perforin recruit response treatment response tumor tumor growth tumorigenesis

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