Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: Dec. 8, 2022

Abstract Many types of human cells self-destruct to maintain biological homeostasis and defend the body against pathogenic substances. This process, called regulated cell death (RCD), is important for various activities, including clearance aberrant cells. Thus, RCD pathways represented by apoptosis have increased in importance as a target development cancer medications recent years. However, because tumor show avoidance apoptosis, which causes treatment resistance recurrence, numerous studies been devoted alternative mortality processes, namely necroptosis, pyroptosis, ferroptosis, cuproptosis; these modalities extensively studied shown be crucial therapy effectiveness. Furthermore, evidence suggests that undergoing may alter immunogenicity microenvironment (TME) some extent, rendering it more suitable inhibiting progression metastasis. In addition, other components TME undergo abovementioned forms induce immune attacks on cells, resulting enhanced antitumor responses. Hence, this review discusses molecular processes features cuproptosis effects novel proliferation Importantly, introduces complex affect biology. It also summarizes potential agents nanoparticles or inhibit their therapeutic based from vivo vitro reports clinical trials inducers evaluated treatments patients. Lastly, we summarized impact modulating drug advantages adding modulators over conventional treatments.

Language: Английский

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Cuproptosis-Related MiR-21-5p/FDX1 Axis in Clear Cell Renal Cell Carcinoma and Its Potential Impact on Tumor Microenvironment

Cells, Journal Year: 2022, Volume and Issue: 12(1), P. 173 - 173

Published: Dec. 31, 2022

As a newly identified type of programmed cell death, cuproptosis may have an impact on cancer development, including clear renal carcinoma (ccRCC). Herein, we first noticed that the expression levels regulators exhibited tight correlation with clinicopathological characteristics ccRCC. The cuproptosis-sensitive sub-type (CSS), classified via consensus clustering analysis, harbored higher overall survival rate compared to cuproptosis-resistant (CRS), which resulted from differential infiltration immune cells. FDX1, master regulator, was experimentally determined as tumor suppressor in ccRCC cells by suppressing growth and invasion ACHN OSRC-2 cuproptosis-dependent -independent manner. results IHC staining also demonstrated FDX1 negatively correlated initiation progression. Furthermore, miR-21-5p/FDX1 axis verified miR-21-5p directly binds 3′-UTR mediate its degradation. Consequently, inhibitor suppressed cells, could be compensated knockdown, reinforcing functional linkage between Finally, evaluated microenvironment under noted this strongly associated such CD4+ T Treg macrophages, suggesting signaling alter microenvironmental components drive Overall, study constructed analyzed potential microenvironment, providing valuable insights improve current management.

Language: Английский

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Systematic analysis of integrated bioinformatics to identify upregulated THBS2 expression in colorectal cancer cells inhibiting tumour immunity through the HIF1A/Lactic Acid/GPR132 pathway

Cancer Cell International, Journal Year: 2023, Volume and Issue: 23(1)

Published: Oct. 27, 2023

Abstract Background THBS2, a member of the extracellular matrix glycoprotein family, can effectively inhibit tumour growth and angiogenesis. This study aimed to investigate biological role THBS2 in various types cancers mechanisms underlying malignant progression colorectal cancer (CRC). Methods expression pan-cancer tissues cell lines was assessed using HPA, TISCH CCLE databases. The CIBERSORT, ESTIMATE, TIMER, xCell ssGSEA (implemented IOBR R package) algorithms were used calculate proportion tumour-infiltrating immune cells based on profile TCGA-COAD cohort. clusterprofiler package implement GO KEGG pathway enrichm SNVs compared between high- low-THBS2-expression groups maftools package. Additionally, immunotherapy responses immunophenoscores (IPSs). CT26 engineered overexpress (CT26-THBS2) its regulatory effects HIF1 cellular metabolism. conditioned medium from CT26-THBS2 collected examine effect M2 polarisation RAW264.7 macrophages. Subsequently, vitro experiments performed validate inhibitory M2-polarised macrophages T-cell proliferation cytotoxicity. A tumour-bearing mouse model constructed impact high microenvironment vivo. Results upregulated majority tumours, including COAD, positively associated with ESTIMATEScore, ImmuneScore StromalScore. Furthermore, angiogenesis epithelial–mesenchymal transition negatively DNA repair, cycle replication most tumours. considerably progression-free interval (PFI) MSI COAD. methylation levels remarkably lower COAD than healthy tissues. promoted nuclear translocation consequently enhanced lactate metabolism cells. In vivo revealed that released by macrophages, leading inhibition Conclusions is PFI, infiltration, regulation, death, migration, transition, genomic variations may serve as biomarker for Upregulated CRC inhibits anti-tumour immunity through HIF1A/lactic acid/GPR132 pathway.

Language: Английский

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Cuproptosis-related gene CDKN2A as a molecular target for IPF diagnosis and therapeutics

Inflammation Research, Journal Year: 2023, Volume and Issue: 72(6), P. 1147 - 1160

Published: May 11, 2023

Language: Английский

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The therapeutic and prognostic role of cuproptosis-related genes in triple negative breast cancer

BMC Bioinformatics, Journal Year: 2023, Volume and Issue: 24(1)

Published: May 31, 2023

Abstract Background This study aimed to observe the potential impact of known cuproptosis-related genes (CRGs) on triple negative breast cancer (TNBC) development, as well their associated molecular mechanisms, immune infiltration mechanisms and therapeutic agents. Results Based Cox Proportional Hazard Model, 11 CRGs may be especially important in TNBC development progression (considered Key-TNBC-CRGs). The expression several Key-TNBC-CRGs (e.g., ATP7A, PIK3CA, LIAS, LIPT ) are with common mutations. SCNA variation related differences profiles. In particular, depletion ATP7A , ATP7B CLS LIAS SCL31A1 while high amplification NLRP3 LIPT2 correlated decreased infiltration. our proportional hazards regression model, there is a significant difference overall survival between high-risk low-risk groups. HR group 3.891 versus group. And this model has satisfactory performance Prediction 5–15-year survival, particular 10-year (AUC = 0.836). Finally, we discovered some drugs for treatment based strategy targeting Key-TNBC-CRGs, such Dasatinib combined ABT-737, Erastin or Methotrexate, Docetaxel/Ispinesib combination. Conclusion conclusion, play roles they can tumor microenvironment patient survival. interact mutually influenced by BC-related Additionally, established 11-gene risk robust prediction As well, new proposed potentially effective CRG strategy.

Language: Английский

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The Role of Ferroptosis and Cuproptosis in Tuberculosis Pathogenesis: Implications for Therapeutic Strategies

Current Issues in Molecular Biology, Journal Year: 2025, Volume and Issue: 47(2), P. 99 - 99

Published: Feb. 5, 2025

Tuberculosis (TB) caused by Mycobacterium tuberculosis (M.tb) remains a global health crisis, with over 10 million people affected annually. Despite advancements in treatment, M.tb has developed mechanisms to evade host immune responses, complicating efforts eradicate the disease. Two emerging cell death pathways, ferroptosis and cuproptosis, have been linked TB pathogenesis. Ferroptosis, an iron-dependent form of death, is driven lipid peroxidation reactive oxygen species (ROS) accumulation. This process can limit replication depleting intracellular iron inducing macrophage necrosis. However, excessive may lead tissue damage aid bacterial dissemination. Cuproptosis, triggered copper accumulation, disrupts mitochondrial metabolism, leading protein aggregation death. exploits both metabolism survive within macrophages, manipulating these processes resist oxidative stress responses. review examines roles cuproptosis TB, discussing how manipulates pathways for survival. While therapeutic strategies targeting processes, such as inducers (Erastin, RSL3) inhibitors (Ferrostatin-1) ionophores (Disulfiram, Elesclomol) chelators, show promise, limited understanding potential off-target effects significant challenge. Further exploration provide insights into development targeted therapies aimed at controlling infection while minimizing damage. By elucidating complex interactions between ferroptosis, future could better address resistance improve clinical outcomes.

Language: Английский

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The complexities of cell death mechanisms: a new perspective in systemic sclerosis therapy

APOPTOSIS, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 9, 2025

Language: Английский

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A cuproptosis random forest cox score model-based evaluation of prognosis, mutation characterization, immune infiltration, and drug sensitivity in hepatocellular carcinoma

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: March 30, 2023

Background Hepatocellular carcinoma is the third most deadly malignant tumor in world with a poor prognosis. Although immunotherapy represents promising therapeutic approach for HCC, overall response rate of HCC patients to less than 30%. Therefore, it great significance explore prognostic factors and investigate associated immune microenvironment features. Methods By analyzing RNA-seq data TCGA-LIHC cohort, set cuproptosis related genes was extracted via correlation analysis as generalization feature. Then, random forest cox model constructed score built by feature filtering univariate multivariate regression analysis. Subsequently, prognosis prediction CRFCS evaluated independent cohorts from GEO ICGC using KM ROC methods. Moreover, mutation characterization, cell infiltration, evasion, drug sensitivity were assessed. Results A based on four genes. Patients high group exhibited lower survival. Univariate Cox validated an indicator. revealed that good predictor (AUC =0.82). Mutation manifested microsatellite instability (MSI) significantly increased group. Meanwhile, showed displayed much more infiltration compared low The escape assessment demonstrated decreased TIDE indicating probability Interestingly, checkpoints highly expressed Drug had IC 50 sorafenib Conclusions In this study, we (CRFCS) model. be potential indicator samples correlated TME characteristics well clinical treatment efficacy. Importantly, group, may benefit treatment.

Language: Английский

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Single-cell disulfidptosis regulator patterns guide intercellular communication of tumor microenvironment that contribute to kidney renal clear cell carcinoma progression and immunotherapy

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Jan. 16, 2024

Background Disulfidptosis, an emerging type of programmed cell death, plays a pivotal role in various cancer types, notably impacting the progression kidney renal clear carcinoma (KIRC) through tumor microenvironment (TME). However, specific involvement disulfidptosis within TME remains elusive. Methods Analyzing 41,784 single cells obtained from seven samples KIRC single-cell RNA sequencing (scRNA-seq), this study employed nonnegative matrix factorization (NMF) to assess 24 regulators. Pseudotime analysis, intercellular communication mapping, determination transcription factor activities (TFs), and metabolic profiling subgroup were conducted using Monocle, CellChat, SCENIC, scMetabolism. Additionally, public cohorts utilized predict prognosis immune responses KIRC. Results Through NMF clustering differential expression marker genes, fibroblasts, macrophages, monocytes, T cells, B categorized into four six distinct subgroups. Furthermore, investigation revealed correlation between regulatory factors biological traits, as well pseudotime trajectories Notably, disulfidptosis-mediated subgroups (DSTN+CD4T-C1 FLNA+CD4T-C2) demonstrated significant prognostic value patients with Multiple immunohistochemistry (mIHC) assays identified both clusters. Moreover, CellChat analysis unveiled diverse extensive interactions epithelial highlighting TNFSF12-TNFRSF12A ligand-receptor pair mediators DSTN+CD4T-C1, FLNA+CD4T-C2, cells. Conclusion Our sheds light on regulating characteristics TME. These findings offer valuable insights for KIRC, potentially guiding personalized immunotherapy approaches.

Language: Английский

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Deciphering the immune heterogeneity dominated by natural killer cells with prognostic and therapeutic implications in hepatocellular carcinoma

Computers in Biology and Medicine, Journal Year: 2023, Volume and Issue: 158, P. 106872 - 106872

Published: April 4, 2023

Language: Английский

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