Canagliflozin impairs T-cell effector function via metabolic suppression in autoimmunity [Metabolic Pathways]
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ABSTRACT:
PROVIDER: PRJNA952145 | ENA |
REPOSITORIES: ENA
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Project description:Augmented T-cell function leading to host damage in autoimmunity is supported by metabolic dysregulation. Targeting immunometabolism for the treatment of autoimmunity by repurposing clinically approved metabolic modulators, such as those used to treat people with type 2 diabetes (T2D), is therefore an attractive avenue. Canagliflozin, a class of the newest type of T2D drug – sodium glucose co-transporter 2 (SGLT2) inhibitors – has known off-target effects including mitochondrial glutamate dehydrogenase (GDH) and complex I inhibition. To date, the effects of SGLT2 inhibitors on human T-cell function are extremely limited. Here, we analysed 748 genes using the Nanostring nCounter® Metabolic Pathways Panel and discovered 38 genes that were differentially regulated between canagliflozin-treated (cana, C; n = 6) and DMSO vehicle control (V; n = 6) T-cells. Of these genes, 24 were downregulated, whilst 14 were upregulated. Notably, 17 of the 24 genes that were downregulated following canagliflozin treatment were associated with the cell cycle, whilst SMAD3 was the only cell cycle-associated gene upregulated by canagliflozin. These analyses allowed a greater understanding of the global changes in T-cell metabolism that occur in response to treatment with SGLT2 inhibitors.
2023-04-04 | GSE228910 | GEO
Project description:Canagliflozin impairs T-cell effector function via metabolic suppression in autoimmunity.
| PRJNA952139 | ENA
Project description:Augmented T-cell function leading to host damage in autoimmunity is supported by metabolic dysregulation. Targeting immunometabolism for the treatment of autoimmunity by repurposing clinically approved metabolic modulators, such as those used to treat people with type 2 diabetes (T2D), is therefore an attractive avenue. Canagliflozin, a class of the newest type of T2D drug – sodium glucose co-transporter 2 (SGLT2) inhibitors – has known off-target effects including mitochondrial glutamate dehydrogenase (GDH) and complex I inhibition. To date, the effects of SGLT2 inhibitors on human T-cell function are extremely limited. Here, we analysed 784 genes using the Nanostring nCounter® Autoimmune Profiling Panel and discovered 42 genes that were differentially regulated between canagliflozin-treated (cana, C; n = 6) and DMSO vehicle control (V; n = 6) T-cells. Of these genes, 39 were downregulated, including IL2, CSF2 and CCL20; whilst 3 were upregulated, including SELL. Dapagliflozin was used as another control, as this SGLT2 inhibitor does not exhibit any known off-target effects like canagliflozin. Here, there were no differentially expressed genes between dapagliflozin-treated (dapa, D; n = 4) and DMSO vehicle control (V; n = 4) T-cells. These analyses allowed a greater understanding of the global changes in T-cell function that occur in response to treatment with SGLT2 inhibitors.
2023-04-04 | GSE228909 | GEO
Project description:Canagliflozin impairs T-cell effector function via metabolic suppression in autoimmunity [Autoimmune Profiling]
| PRJNA952144 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-04-04 | GSE228911 | GEO
Project description:Non-small cell lung cancer (NSCLC) has a poor prognosis and effective therapeutic strategies are lacking. The diabetes drug canagliflozin inhibits NSCLC cell proliferation and the mammalian target of rapamycin (mTOR) pathway, which mediates cell growth and survival, but it is unclear whether this drug can enhance response rates when combined with cytotoxic therapy. Here, we evaluated the effects of canagliflozin on human NSCLC response to cytotoxic therapy in tissue cultures and xenografts. Ribonucleic acid sequencing (RNA-seq), real-time quantitative PCR (RT-qPCR), metabolic function, small interfering ribonucleic acid (siRNA) knockdown and protein expression assays were used in mechanistic analyses. We found that canagliflozin inhibited proliferation and clonogenic survival of NSCLC cells, and augmented the efficacy of radiotherapy to mediate these effects and inhibit NSCLC xenograft growth. Canagliflozin treatment alone moderately inhibited mitochondrial oxidative phosphorylation and exhibited greater anti-proliferative capacity than specific mitochondrial complex-I inhibitors. The treament downregulated genes mediating hypoxia-inducible factor (HIF)-1a stability, metabolism and survival, activated adenosine monophosphate-activated protein kinase (AMPK) and inhibited mTOR, a critical activator of HIF-1a signaling. HIF-1a knockdown and stabilization experiments suggested that canagliflozin mediates anti-proliferative effects, in part, through suppression of HIF-1a. Transcriptional regulatory network analysis pinpointed histone deacetylase 2 (HDAC2), a gene suppressed by canagliflozin, as a key mediator of canagliflozin’s transcriptional reprogramming. HDAC2 knockdown eliminated HIF-1a levels and enhanced the anti-proliferative effects of canagliflozin. HDAC2-regulated genes suppressed by canagliflozin are associated with poor prognosis in several clinical NSCLC datasets. In addition, we include evidence that canagliflozin also improves NSCLC response to chemotherapy. In summary, canagliflozin may be a promising therapy to develop in combination with cytotoxic therapy in NSCLC.
2023-08-17 | GSE239495 | GEO
Project description:Radiotherapy (RT) is a non-invasive standard treatment for prostate cancer (PC). However, PC develops radio-resistance, highlighting a need for agents to improve RT response. Canagliflozin, an inhibitor of sodium-glucose co-transporter-2, is approved for use in diabetes and heart failure, but is also shown to inhibit PC growth. However, whether canagliflozin can improve RT response in PC remains unknown. Here, we show that well-tolerated doses of canagliflozin suppress proliferation and survival of androgen-sensitive and insensitive human PC cells and tumors and sensitize them to RT. Canagliflozin blocks mitochondrial respiration, promotes AMPK activity, inhibits the MAPK and mTOR-p70S6k/4EBP1 pathways, activates cell cycle checkpoints, and inhibits proliferation in part through HIF-1 suppression. Canagliflozin mediates transcriptional reprogramming of several metabolic and survival pathways known to be regulated by ETS and E2F family transcription factors. Genes downregulated by canagliflozin are associated with poor PC prognosis. This study lays the groundwork for clinical investigation of canagliflozin in PC prevention and treatment in combination with RT.
2023-09-10 | GSE239688 | GEO
Project description:We found canagliflozin shows elimination of senescent cells from organs in age-related pathology mouse model including diabetes. To clarify detailed change by canagliflozin treatement, we conducted RNA-seq analysis in gonadal white adipose tissue(gWAT).
2024-04-06 | GSE252539 | GEO
Project description:We assessed the change in hepatic transciptional pattern after treatment with SGLT-2 inhibitors canagliflozin in a mice model of diet-induced obesity. Pharmacologic inhibition of the renal sodium/glucose cotransporter-2 induces glycosuria and reduces glycemia. Given that SGLT2 inhibitors (SGLT2i) reduce mortality and CV risk in T2D, improved understanding of molecular mechanisms mediating these metabolic effects is required. Treatment of obese but nondiabetic mice with the SGLT2i canagliflozin (CANA) reduces adiposity, improves glucose tolerance despite reduced plasma insulin, increases plasma ketones, and improves plasma lipid profiles. We utilized an integrated transcriptomic-metabolomics approach to demonstrate that CANA modulates key nutrient-sensing pathways, with activation of AMPK and inhibition of mTOR, independent of insulin or glucagon sensitivity or signaling. Moreover, CANA induces transcriptional reprogramming to activate catabolic pathways, increase fatty acid oxidation, reduce hepatic steatosis and diacylglycerol content, and increase hepatic and plasma levels of FGF21. Taken together, these data demonstrate that SGLT-2 inhibition triggers a fasting-like transcriptional and metabolic paradigm.
2020-04-16 | GSE148702 | GEO
Project description:The impact of canagliflozin on gene expression changes was investigated in human renal proximal tubular cells (HK2) after pre-treatment with high glucose.
2019-02-27 | GSE106156 | GEO