Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 19, 2023

Abstract The Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved mechanism transmembrane transduction that enables cells to communicate with the exterior environment. Various cytokines, interferons, growth factors, other specific molecules activate JAK-STAT signaling drive a series physiological pathological processes, including proliferation, metabolism, immune response, inflammation, malignancy. Dysregulated related genetic mutations are strongly associated activation cancer progression. Insights into structures functions have led development approval diverse drugs for clinical treatment diseases. Currently, been developed mainly target commonly divided three subtypes: cytokine or receptor antibodies, JAK inhibitors, STAT inhibitors. And novel agents also continue be tested in preclinical studies. effectiveness safety each kind drug warrant further scientific trials before put being applications. Here, we review current understanding fundamental composition function pathway. We discuss advancements JAK-STAT–related pathogenic mechanisms; targeted therapies various diseases, especially disorders, cancers; newly inhibitors; challenges directions field.

Language: Английский

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Single-cell sequencing analysis related to sphingolipid metabolism guides immunotherapy and prognosis of skin cutaneous melanoma

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

Published: Nov. 23, 2023

Background We explore sphingolipid-related genes (SRGs) in skin melanoma (SKCM) to develop a prognostic indicator for patient outcomes. Dysregulated lipid metabolism is linked aggressive behavior various cancers, including SKCM. However, the exact role and mechanism of sphingolipid remain partially understood. Methods integrated scRNA-seq data from patients sourced GEO database. Through utilization Seurat R package, we successfully identified distinct gene clusters associated with survival data. Key were through single-factor Cox analysis used model using LASSO stepwise regression algorithms. Additionally, evaluated predictive potential these within immune microenvironment their relevance immunotherapy. Finally, validated functional significance high-risk IRX3 vitro experiments. Results Analysis expression patterns 4 specific diverse cell subpopulations. Re-clustering cells based on increased SRG revealed 7 subgroups significant implications. Using marker genes, lasso, regression, selected 11 construct risk signature. This signature demonstrated strong correlation infiltration stromal scores, highlighting its tumor microenvironment. Functional studies involving knockdown A375 WM-115 showed reductions viability, proliferation, invasiveness. Conclusion SRG-based holds promise precise prognosis. An in-depth exploration characteristics offers insights into immunotherapy response. Therapeutic targeting may benefit patients.

Language: Английский

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HKDC1 promotes tumor immune evasion in hepatocellular carcinoma by coupling cytoskeleton to STAT1 activation and PD-L1 expression

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 13, 2024

Abstract Immune checkpoint blockade (ICB) has shown considerable promise for treating various malignancies, but only a subset of cancer patients benefit from immune inhibitor therapy because evasion and immune-related adverse events (irAEs). The mechanisms underlying how tumor cells regulate cell response remain largely unknown. Here we show that hexokinase domain component 1 (HKDC1) promotes in CD8 + T cell-dependent manner by activating STAT1/PD-L1 cells. Mechanistically, HKDC1 binds to presents cytosolic STAT1 IFNGR1 on the plasma membrane following IFNγ-stimulation associating with cytoskeleton protein ACTA2, resulting phosphorylation nuclear translocation. inhibition combination anti-PD-1/PD-L1 enhances vivo antitumor liver models male mice. Clinical sample analysis indicates correlation among expression, phosphorylation, survival hepatocellular carcinoma treated atezolizumab (anti-PD-L1). These findings reveal role regulating coupling activation, providing potential strategy enhance responses.

Language: Английский

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PROTACs: A novel strategy for cancer drug discovery and development

MedComm, Journal Year: 2023, Volume and Issue: 4(3)

Published: May 29, 2023

Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: small molecule that binds to target protein, an E3 ligase ligand (consisting and its recruiter), chemical linker hooks first two components together. In the past 20 years, we have witnessed advancement multiple degraders into clinical trials anticancer therapies. However, one major challenges is only very limited number recruiters are currently available as targeted protein degradation (TPD), although human genome encodes more than 600 ligases. Thus, there urgent need identify additional effective TPD applications. this review, summarized existing RING-type ubiquitin their act ligands application discovery. We believe review could serve reference future development efficient cancer discovery development.

Language: Английский

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Single-cell analyses reveal cannabidiol rewires tumor microenvironment via inhibiting alternative activation of macrophage and synergizes with anti-PD-1 in colon cancer

Journal of Pharmaceutical Analysis, Journal Year: 2023, Volume and Issue: 13(7), P. 726 - 744

Published: April 23, 2023

Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy. Cannabidiol (CBD) is a non-psychoactive natural active ingredient the cannabis plant has various pharmacological effects, including neuroprotective, antiemetic, anti-inflammatory, and antineoplastic activities. This study aimed elucidate specific anticancer mechanism of CBD by single-cell RNA sequencing (scRNA-seq) ATAC (scATAC-seq) technologies. Here, we report inhibits colorectal cancer progression modulating suppressive tumor (TME). Our transcriptome results showed suppressed M2-like macrophages promoted M1-like in both strength quantity. Furthermore, significantly enhanced interaction between cells restored intrinsic anti-tumor properties macrophages, thereby preventing progression. Mechanistically, altered metabolic pattern related signaling pathways. We found inhibited alternative activation shifted process oxidative phosphorylation fatty acid oxidation glycolysis inhibiting phosphatidylinositol 3-kinase-protein kinase B pathway downstream target genes. CBD-mediated macrophage plasticity response anti-programmed cell death protein-1 (PD-1) immunotherapy xenografted mice. Taken together, provide new insights into effects CBD.

Language: Английский

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Recent Advances in Reprogramming Strategy of Tumor Microenvironment for Rejuvenating Photosensitizers‐Mediated Photodynamic Therapy

Small, Journal Year: 2023, Volume and Issue: 20(16)

Published: Nov. 28, 2023

Abstract Photodynamic therapy (PDT) has recently been considered a potential tumor due to its time‐space specificity and non‐invasive advantages. PDT can not only directly kill cells by using cytotoxic reactive oxygen species but also induce an anti‐tumor immune response causing immunogenic cell death of cells. Although it exhibits promising prospect in treating tumors, there are still many problems be solved practical application. Tumor hypoxia immunosuppressive microenvironment seriously affect the efficacy PDT. The hypoxic is mainly abnormal vascular matrix around tumor, metabolism, influence various immunosuppressive‐related their expressed molecules. Thus, reprogramming (TME) great significance for rejuvenating This article reviews latest strategies PDT, from regulating matrix, interfering with related factors reverse microenvironment. These provide valuable information better understanding TME guide development next‐generation multifunctional nanoplatforms

Language: Английский

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Ruxolitinib induces apoptosis and pyroptosis of anaplastic thyroid cancer via the transcriptional inhibition of DRP1-mediated mitochondrial fission

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(2)

Published: Feb. 9, 2024

Abstract Anaplastic thyroid carcinoma (ATC) has a 100% disease-specific mortality rate. The JAK1/2-STAT3 pathway presents promising target for treating hematologic and solid tumors. However, it is unknown whether the activated in ATC, anti-cancer effects mechanism of action its inhibitor, ruxolitinib (Ruxo, clinical JAK1/2 inhibitor), remain elusive. Our data indicated that signaling significantly upregulated ATC tumor tissues than normal papillary cancer tissues. Apoptosis GSDME-pyroptosis were observed cells following vitro vivo administration Ruxo. Mechanistically, Ruxo suppresses phosphorylation STAT3, resulting repression DRP1 transactivation causing mitochondrial fission deficiency. This deficiency essential activating caspase 9/3-dependent apoptosis GSDME-mediated pyroptosis within cells. In conclusion, our findings indicate directly regulated transactivated by STAT3; this exhibits novel crucial aspect on regulation dynamics. transcriptional inhibition hampered division triggered through mechanisms. These results provide compelling evidence potential therapeutic effectiveness ATC.

Language: Английский

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Nanomaterials-Involved Tumor-Associated Macrophages’ Reprogramming for Antitumor Therapy

ACS Nano, Journal Year: 2024, Volume and Issue: 18(11), P. 7769 - 7795

Published: Feb. 29, 2024

Tumor-associated macrophages (TAMs) play pivotal roles in tumor development. As primary contents of environment (TME), TAMs secrete inflammation-related substances to regulate tumoral occurrence and There are two kinds TAMs: the tumoricidal M1-like protumoral M2-like TAMs. Reprogramming from immunosuppressive M2 immunocompetent M1 phenotype is considered a feasible way improve immunotherapeutic efficiency. Notably, nanomaterials show great potential for biomedical fields due their controllable structures properties. many types that exhibit regulatory activities TAMs' reprogramming. In this review, recent progress nanomaterials-involved reprogramming comprehensively discussed. The various strategies summarized introduced. Additionally, challenges perspectives efficient therapy discussed, aiming provide inspiration regulator design promote development TAMs-mediated immunotherapy.

Language: Английский

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WP1066, a small molecule inhibitor of STAT3, chemosensitizes paclitaxel-resistant ovarian cancer cells to paclitaxel by simultaneously inhibiting the activity of STAT3 and the interaction of STAT3 with Stathmin

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 221, P. 116040 - 116040

Published: Feb. 3, 2024

Language: Английский

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Oligo-PROTAC strategy for cell-selective and targeted degradation of activated STAT3

Molecular Therapy — Nucleic Acids, Journal Year: 2024, Volume and Issue: 35(1), P. 102137 - 102137

Published: Feb. 5, 2024

Decoy oligodeoxynucleotides (ODNs) allow targeting undruggable transcription factors, such as STAT3, but their limited potency and lack of delivery methods hampered translation. To overcome these challenges, we conjugated a STAT3-specific decoy to thalidomide, ligand cereblon in E3 ubiquitin ligase complex, generate proteolysis-targeting chimera (STAT3D

Language: Английский

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