Network-based screening identifies sitagliptin as an antitumor drug targeting dendritic cells
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ABSTRACT:
PROVIDER: PRJNA876933 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21424379_1.fastq.gz | Fastqsanger.gz | |||
| SRR21424379_2.fastq.gz | Fastqsanger.gz | |||
| SRR21424380_1.fastq.gz | Fastqsanger.gz | |||
| SRR21424380_2.fastq.gz | Fastqsanger.gz | |||
| SRR21424381_1.fastq.gz | Fastqsanger.gz |
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Project description:Dendritic cell (DC)-mediated antigen presentation is essential for the priming and activation of tumor-specific T cells. However, few drugs that specifically manipulate DC functions are available. Here, we observed that DCs initiated a distinct transcriptional program during antigen presentation. We utilized a network-based approach to screen for DC-targeting therapeutics. Sitagliptin, an oral gliptin widely used for type 2 diabetes, was identified as a drug that targets DCs. In mouse models, sitagliptin inhibited tumor growth by enhancing DC-mediated antigen presentation, leading to better T cell activation.
2024-02-21 | GSE212712 | GEO
Project description:BackgroundDendritic cell (DC)-mediated antigen presentation is essential for the priming and activation of tumor-specific T cells. However, few drugs that specifically manipulate DC functions are available. The identification of drugs targeting DC holds great promise for cancer immunotherapy.MethodsWe observed that type 1 conventional DCs (cDC1s) initiated a distinct transcriptional program during antigen presentation. We used a network-based approach to screen for cDC1-targeting therapeutics. The antitumor potency and underlying mechanisms of the candidate drug were investigated in vitro and in vivo.ResultsSitagliptin, an oral gliptin widely used for type 2 diabetes, was identified as a drug that targets DCs. In mouse models, sitagliptin inhibited tumor growth by enhancing cDC1-mediated antigen presentation, leading to better T-cell activation. Mechanistically, inhibition of dipeptidyl peptidase 4 (DPP4) by sitagliptin prevented the truncation and degradation of chemokines/cytokines that are important for DC activation. Sitagliptin enhanced cancer immunotherapy by facilitating the priming of antigen-specific T cells by DCs. In humans, the use of sitagliptin correlated with a lower risk of tumor recurrence in patients with colorectal cancer undergoing curative surgery.ConclusionsOur findings indicate that sitagliptin-mediated DPP4 inhibition promotes antitumor immune response by augmenting cDC1 functions. These data suggest that sitagliptin can be repurposed as an antitumor drug targeting DC, which provides a potential strategy for cancer immunotherapy.
| S-EPMC10921530 | biostudies-literature
Project description:Dendritic cell (DC)-mediated antigen presentation is essential for the priming and activation of tumor-specific T cells. However, few drugs that specifically manipulate DC functions are available. Here, we observed that DCs initiated a distinct transcriptional program during antigen presentation. We utilized a network-based approach to screen for DC-targeting therapeutics. Sitagliptin, an oral gliptin widely used for type 2 diabetes, was identified as a drug that targets DCs. In mouse models, sitagliptin inhibited tumor growth by enhancing DC-mediated antigen presentation, leading to better T cell activation.
2024-02-21 | GSE228128 | GEO
Project description:Aim: To investigate the effect and mechanism of Sitagliptin phosphate on inflammation and macrophage polarization in a mouse model of type 2 diabetes. Methods: In vitro, Raw264.7 cells were cultured with a high concentration of glucose (HG) and sitagliptin phosphate (SIG). The levels of inflammatory factors and the regulation of macrophage polarization were investigated, and the differentially expressed genes between HG and HG+SIG intervention were analyzed and enriched through transcriptomics. In vivo, C57BL/6J male mice were treated with HFD+STZ to establish a type 2 diabetes mouse model were investigated the effects of regulation of macrophage polarization in the pancreas and visceral adipose tissue. Results:In vitro cell experiments and transcriptomics showed that Sitagliptin phosphate decreased the secretion of inflammatory factors IL-6 and TNF-α induced by high-glucose, and increased secretion of anti-inflammatory factor IL-10 by enhancing macrophage polarization. In vivo, the body weight and abdominal visceral fat weight, the ratio of visceral fat weight to body weight and fasting blood glucose were significantly increased in the DM group compared with the Control (P<0.05), Sitagliptin phosphate treatments reversed the changes in the DM group. Moreover, histological analysis showed that compared with the Control group, the size of visceral adipocytes, hepatocyte lipid deposition and the ratio of M1/M2 macrophage were higher in the DM group, which were reversed by Sitagliptin phosphate treatments (P<0.05), insulin treatments did not have a significant effect(P＞0.05).Mechanistically, Western blot showed that compared with the normal group, HG upregulated the expression of mTORc1 protein, P-65 phosphorylation and P-65 protein expression in Raw264.7 cells (P<0.05), downregulated the expression of IKKβ (P<0.05) and PPAR-γ proteins (P<0.05), Sitagliptin phosphate and insulin treatments rescued these changes. Conclusion: These results indicated that Sitagliptin phosphate reduced high glucose-induced inflammation by improving the imbalance of macrophage polarization via modulating the mTORc1/ PPAR-γ/NF-κB in vitro and in vivo.
2025-04-03 | GSE293313 | GEO
Project description:To identify the cellular proteins that interact with Sitagliptin, we performed SPIDER coupled with SILAC-based mass spectrometry using two kinds of Sitagliptin containing different PEG linkers (namely, biotin-PEG3-Sitagliptin and biotin-PEG5-Sitagliptin) incubated with HEK293T cell lysate.
2021-06-04 | PXD026524 |
Project description:To investigated the therapeutic mechanism underlying the sitagliptin improves vascular endothelial function in obesity, we performed bioinformatics analyses on the expression profiles of long noncoding RNAs (lncRNAs) and message RNAs (mRNAs) in the aortae from obese mice with or without sitagliptin treatment.
2022-04-19 | GSE200814 | GEO
Project description:The aim of the study was to explore the effect of topically administered sitagliptin, an inhibitor of the enzyme dipeptidyl peptidase-4, on the retinal expression patterns of an experimental model of DR. Background: Synaptic dysfunction and neuronal damage have been extensively associated with diabetic retinopathy (DR). Our group evidenced that chronic hyperglycemia reduces the retinal expression of presynaptic proteins, which are crucial for a proper synaptic function. The aim of the study was to explore the effect of topically administered sitagliptin, an inhibitor of the en-zyme dipeptidyl peptidase-4, on the retinal expression patterns of an experimental model of DR. Methods: Transcriptome analysis was performed comparing the retinas of 10 diabetic (db/db) mice randomly treated with sitagliptin eye drops (10 mg/mL) twice daily, and the reti-nas of 10 additional db/db mice that received vehicle eye drops. 10 non diabetic mice (db/+) were used as control group. Gene Ontology (GO) and Reactome databases were used to assess the Gene Set Enrichment Analysis (GSEA) in order to explore the most enriched biological pathways among groups. The most differentiated genes of these pathways were validated through quantitative RT-PCR. Results: Transcriptome analysis revealed that sitagliptin eye drops have a significant effect on retinal expression patterns and that neurotransmission was the most enriched biological process. Our study evidenced enriched pathways that contain genes involved in membrane trafficking, transmission across chemical synapses, vesi-cle-mediated transport, neurotransmitter receptors and postsynaptic signal transmission with negative regulation of signaling as a consequence of neuroprotector treatment with sitagliptin. This improves the modulation of macromolecule biosynthetic process with positive regulation of cell communication which provides beneficial effects for neuronal metabolism. Conclu-sions: This study suggests that topical administration of sitagliptin ameliorates the abnormali-ties on presynaptic and postsynaptic signal transmission during experimental DR, and that this improvement is one of the main mechanisms behind the previously demonstrated beneficial effects.
2023-01-11 | GSE219084 | GEO
Project description:Targeting WEE1 in tumor-associated dendritic cells potentiates antitumor immunity
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Project description:More and more evidence shows that maternal overnutrition may increase the risk of diabetes in offspring. This study aimed to find out whether maternal early sitagliptin intervention improves glucose intolerance through gut target in offspring.
2020-04-10 | GSE134070 | GEO
Project description:Vaccination induces immunostimulatory signals which are often accompanied by regulatory mechanisms such as IL-10, which control T-cell activation and inhibit vaccine-dependent antitumor therapeutic effect. Thus, here we characterized IL-10-producing cells treated with therapeutic vaccines. Although several cell subsets produced IL-10 irrespective of treatment, an early vaccine-dependent induction of IL-10 was detected in dendritic cells (DC). IL-10 production defined a DC population characterized by a poorly mature phenotype, lower expression of T-cell stimulating molecules and upregulation of PD-L1. These IL-10+ DC showed impaired in vitro T-cell stimulatory capacity, which was rescued by incubation with IL-10R and PD-L1-inhibiting antibodies. In vivo IL-10 blockade during vaccination decreased the proportion of IL-10+ DC and improved their maturation, without modifying PD-L1 expression. Similarly, PD-L1 blockade did not affect IL-10 expression, suggesting independent regulation of these molecules. Interestingly, vaccination combined with simultaneous blockade of IL-10 and PD-L1 induced stronger immune responses, resulting in a higher therapeutic efficacy in tumor-bearing mice. These results show that vaccine-induced immunoregulatory DC with dual expression of IL-10 and PD-L1 impair priming of antitumor immunity, suggesting that therapeutic vaccination protocols may benefit from combined targeting of these molecules.
2017-06-10 | GSE84980 | GEO