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Canagliflozin impairs T-cell effector function via metabolic suppression in autoimmunity [Metabolic Pathways]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228910 | GEO | 2023/04/04

REPOSITORIES: GEO

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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.

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Canagliflozin impairs T-cell effector function via metabolic suppression in autoimmunity [Metabolic Pathways]

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