ROS-Responsive Potassium Ionophore-Based Nanoplatform Potentiates Cancer Pyroptosis-Immunotherapy via ER Stress
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PROVIDER: PRJNA1078369 | ENA |
REPOSITORIES: ENA
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Project description:Pyroptosis is an emerging programmed cell death with great potential in antitumor immunotherapy. However, the actual application of pyroptosis is hampered by its nonspecificity and inefficiency. In this study, a reactive oxygen species (ROS) responsive potassium (K+) ionophore-based nanoplatform rPPAA18C6 is constructed based on the triblock polymers PEG-PPBAEM-PAA18C6 to potentiate cancer pyroptosis and immunotherapy via the K+ metabolic disturbance mediated endoplasmic reticulum (ER) stress. The PEG (P) is used to prolong the circulation time in vivo, PPBAEM (r) is used to target the tumor cells and responds to the higher ROS, and PAA18C6 is used to perturb of K+ homeostasis. Moreover, rPPAA18C6 can also function as a drug carrier for chemodrug (doxorubicin, Dox). We find that rPPAA18C6@Dox provokes immune responses in melanoma (B16F10) via pyroptosis-related immunogenic cell death (ICD), in which damage-associated molecular patterns (DAMPs) are released to promote maturation of dendritic cells (DCs), activate cytotoxic T lymphocytes (CTLs), and convert immunosuppressive “cold” tumor to immunogenic “hot” tumor. Moreover, the combined therapy with anti-PD-L1 exhibits apparent tumor suppression far more than expected, suggesting a powerful candidate of rPPAA18C6@Dox for high-efficient immune checkpoint blockade (ICB) therapy. This study thus provides a promising strategy to specifically initiate pyroptosis and potentiate immunotherapy by perturbation of K+ metabolism via a smart nanoplatform.
2025-01-01 | GSE256169 | GEO
Project description:The process of pyroptosis is mediated by inflammasomes and a downstream effector known as gasdermin D (GSDMD). Upon cleavage by inflammasome-associated caspases, the N-terminal domain of GSDMD forms membrane pores that promote cytolysis. Numerous proteins promote GSDMD cleavage, but none are known to be required for pore formation after GSDMD cleavage. Herein, we report a forward genetic screen that identified the Ragulator-Rag complex as being necessary for GSDMD pore formation and pyroptosis in macrophages. Mechanistic analysis revealed that Ragulator-Rag is not required for GSDMD cleavage upon inflammasome activation, but rather promotes GSDMD oligomerization in the plasma membrane. Defects in GSDMD oligomerization and pore formation can be rescued by mitochondrial poisons that stimulate reactive oxygen species (ROS) production, and ROS modulation impacts the ability of inflammasome pathways to promote pore formation downstream of GSDMD cleavage. These findings reveal an unexpected link between key regulators of immunity (inflammasome-GSDMD) and metabolism (Ragulator-Rag).
2021-06-29 | GSE179089 | GEO
Project description:Pyroptosis is a recently discovered form of lytic cell death that is characterized by cell swelling and formation of pores and large bubbles on the plasma membrane. We find radiation could induce pyroptosis in human colorectal cancer HCT116 cells, and irradiation induces pyroptosis in mouse normal intestine MODEK cells only after 36 hours and over 8.0 Gy. In view of the significant pyroptosis effect of MODE-K cells, we selected 4Gy and 12Gy, 24h and 48h for experiments. After ONT full-length transcriptome sequencing, the cell pyroptosis model can screen out the differential genes related to cell pyroptosis, which is helpful to further explore the mechanism of pyroptosis of MODE-K cells.
2024-08-01 | GSE211709 | GEO
Project description:Biomimetic nanococrystals are prepared using the preferred combination of mitoxantrone and gambogic acid for rational drug delivery. The unique mechanism of obtained nanococrystals regulating pyroptosis genes through ribosomal stress is revealed by TMT-proteomics of 4T1 cells.
2024-07-27 | PXD053939 | Pride
Project description:Acidic tumor microenvironment (TME)-evoked MRC nanoparticles (MRC NPs) co-delivering immune agonist RGX-104 and photosensitizer chlorine e6 (Ce6) are reported for pyroptosis-mediated immunotherapy. RGX-104 remodels TME by transcriptional activation of ApoE to regress myeloid-derived suppressor cells’ (MDSCs) activity, which neatly creates foreshadowing for intensifying pyroptosis. Considering Ce6-triggered photodynamic therapy (PDT) can strengthen oxidative stress and organelles destruction to increase immunogenicity, immunomodulatory-photodynamic MRC nanodrugs will implement an aforementioned two-pronged strategy to enhance gasdermin E (GSDME)-dependent pyroptosis. RNA-seq analysis of MRC at the cellular level is introduced to first elucidate the intimate relationship between RGX-104 acting on LXR/ApoE axis and pyroptosis, where RGX-104 provides the prerequisite for pyroptosis participating in antitumor therapy. Briefly, MRC with favorable biocompatibility tackles the obstacle of hydrophobic drugs delivery, and becomes a powerful pyroptosis inducer to reinforce immune efficacy. MRC-elicited pyroptosis in combination with anti-PD-1 blockade therapy boosts immune response in solid tumors, successfully arresting invasive metastasis and extending survival based on remarkable antitumor immunity. MRC may initiate a new window for immuno-photo pyroptosis stimulators augmenting pyroptosis-based immunotherapy. Owing to the transcriptome sequencing on 4T1 cells exposed to various treatment, pyroptosis mechanism of MRC was thoroughly analyzed via comparing the expression discrepancy among PBS, MRC, and MRC+L groups.
2023-08-13 | GSE240328 | GEO
Project description:Pyroptosis—inflammatory cell death mediated by gasdermins (GSDM)—plays crucial roles in antimicrobial defense and inflammatory diseases. Pyroptosis results in the release of proinflammatory molecules, including damage-associated molecular patterns (DAMPs). However, our understanding of the consequences of pyroptosis—especially beyond IL-1 cytokines and DAMPs—that govern inflammation is limited. Here, we show intercellular propagation of pyroptosis from dying cells to bystander cells in vitro and in vivo. We identified extracellular vesicles (EVs) released by pyroptosing cells as the propagator of lytic death to naïve cells, triggering inflammatory responses and tissue damage. Remarkably, DNA-PAINT super-resolution and immunoelectron microscopical analyses revealed the presence of GSDMD nanostructures, such as pores, on EVs released by pyroptotic cells. Importantly, the transplantation of these GSDMD pores on adjacent cells’ plasma membrane by EVs causes cell-extrinsic lysis of bystanders. Overall, our findings demonstrate that cell-to-cell vesicular transplantation of GSDMD pores disseminates pyroptosis, revealing a domino-like effect shaping disease-associated bystander cell death.
2025-01-07 | GSE277224 | GEO
Project description:In this study we investigated the transcriptional response of the yeast Saccharomyces cerevisiae to potassium starvation. To this end yeast cells were grown for 60 min in media without potassium or in media with a standard potassium concnetration (50 mM KCl). Using Serial Analysis of Gene Expression (SAGE)-tag sequencing the effect of potassium starvation on the transcriptome was determined.
2014-12-11 | GSE57093 | GEO
Project description:In this study we investigated the transcriptional response of the yeast Saccharomyces cerevisiae to potassium starvation. To this end yeast cells were grown for 60 min in media without potassium or in media with a standard potassium concnetration (50 mM KCl). Using Serial Analysis of Gene Expression (SAGE)-tag sequencing the effect of potassium starvation on the transcriptome was determined. 4 samples of cells grown in media without potassium and 4 samples of cells grown in the presence of potassium were analyzed.
2014-12-11 | E-GEOD-57093 | biostudies-arrayexpress
Project description:Macrophages are involved in the pathophysiology of many diseases as critical cells of the innate immune system. Pyroptosis is a form of macrophage death that induces cytokinesis of phagocytic substances in the macrophages, thereby defending against infection. Dimethyl itaconate (DI) is an analog of itaconic acid with anti-inflammatory effects. However, the effect of dimethyl itaconate on macrophage pyroptosis has not been elucidated clearly. Thus, the present study aimed to analyze the effect of DI treatment on a macrophage pyroptosis model (Lipopolysaccharide, LPS+Adenosine Triphosphate, ATP). The results showed that 0.25 mM DI ameliorated macrophage pyroptosis and downregulated interleukin (IL)-1β expression. Then, real-time quantitative polymerase chain reaction (RT-qPCR) was used to confirm the result of RNA-sequencing of the upregulated oxidative stress-related genes (Gclc and Gss) and downregulated inflammation-related genes (IL-12β and IL-1β). In addition, Gene Ontology (GO) enrichment analysis showed that differential genes were associated with transcript levels and DNA replication. Kyoto encyclopedia of genes and genomes (KEGG) enrichment showed that signaling pathways, such as tumor necrosis factor (TNF), Jak, Toll-like receptor and IL-17, were altered after DI treatment. N-acetyl-L-cysteine (NAC) reversed the DI effect on the LPS+ATP-induced macrophage pyroptosis and upregulated the IL-1β expression. Oxidative stress-related protein Nrf2 is involved in the DI regulation of macrophage pyroptosis. Taken together, these findings suggested that DI alleviates the pyroptosis of macrophages through oxidative stress.
2021-10-16 | GSE185895 | GEO
Project description:Gasdermin D (GSDMD) is the executioner of pyroptosis, which is important for host defense against pathogen infection. After activation, caspase-mediated cleavage of GSDMD liberates an N-terminal fragment (GSDMD-NT), which oligomerizes and forms pores in the plasma membrane, leading to cell death and subsequent release of proinflammatory cytokines. How this process is spatiotemporally controlled to promote pyroptosis in cells has been a fundamental, unaddressed question. Here, we identify GSDMD as a substrate for reversible S-palmitoylation on cysteine 192 (Cys192) in response to lipopolysaccharide (LPS) stimulation. We found that the palmitoyl acyltransferase DHHC7palmitoylates GSDMD to direct its cleavage by caspases in pyroptosis by promoting the interaction of GSDMD and caspases. We further show that after GSDMD cleavage, palmitoylation of GSDMD-NTpromotes its plasma membrane translocation and binding, and then acyl protein thioesterase 2 (APT2) depalmitoylates GSDMD-NT to unmask the Cys192 residue to promote oxidation-mediated oligomerization and pyroptosis. Perturbation of either palmitoylation or depalmitoylation suppresses pyroptosis, extends the survival of mice from LPS-induced lethal septic shock and sensitizes mice to bacterial infection. Thus. our findings reveal a model through which a palmitoylation-depalmitoylationrelay spatially and temporally controls GSDMD activation in pyroptosis.
2024-02-25 | GSE252911 | GEO