SGK1 signaling promotes glucose metabolism and survival in extracellular matrix detached cells

Mason, Joshua; Cockfield, Jordan A.; Pape, Daniel J.; Meissner, Hannah; Sokolowski, Michael; White, Taylor C.; López, José C. Valentín; Liu, Juan; Liu, Xiaojing; Martínez‐Reyes, Inmaculada; Chandel, Navdeep S.; Locasale, Jason W.; Schafer, Zachary T.

doi:10.1016/j.celrep.2021.108821

Cited by 39 publications

(18 citation statements)

References 44 publications

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“…SGK1 activity and expression are downregulated in the mid-secretory endometrial stromal cells of women suffering from recurrent pregnancy loss 49 , 50 , lung tissues of cecal ligation and puncture (CLP)-induced acute lung injury 51 , and colonic tracts of patients with ulcerative colitis 52 , which sensitizes these patients to inflammation. Moreover, SGK1 is a primary regulator of ion channels and the gene encoding this protein is an important anti-apoptotic gene 53 , 54 . Reduction in SGK1 expression in the VEO of patients with MD may explain some of the features associated with MD, such as the dysregulation of sodium absorption, resulting EH, and increased hair cell loss.…”

Section: Discussionmentioning

confidence: 99%

Serum/glucocorticoid-inducible kinase 1 deficiency induces NLRP3 inflammasome activation and autoinflammation of macrophages in a murine endolymphatic hydrops model

Zhang

Liu

et al. 2023

Nat Commun

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Ménière’s disease, a multifactorial disorder of the inner ear, is characterized by severe vertigo episodes and hearing loss. Although the role of immune responses in Ménière’s disease has been proposed, the precise mechanisms remain undefined. Here, we show that downregulation of serum/glucocorticoid-inducible kinase 1 is associated with activation of NLRP3 inflammasome in vestibular-resident macrophage-like cells from Ménière’s disease patients. Serum/glucocorticoid-inducible kinase 1 depletion markedly enhances IL-1β production which leads to the damage of inner ear hair cells and vestibular nerve. Mechanistically, serum/glucocorticoid-inducible kinase 1 binds to the PYD domain of NLRP3 and phosphorylates it at Serine 5, thereby interfering inflammasome assembly. Sgk−/− mice show aggravated audiovestibular symptoms and enhanced inflammasome activation in lipopolysaccharide-induced endolymphatic hydrops model, which is ameliorated by blocking NLRP3. Pharmacological inhibition of serum/glucocorticoid-inducible kinase 1 increases the disease severity in vivo. Our studies demonstrate that serum/glucocorticoid-inducible kinase 1 functions as a physiologic inhibitor of NLRP3 inflammasome activation and maintains inner ear immune homeostasis, reciprocally participating in models of Ménière’s disease pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Serum/glucocorticoid-inducible kinase 1 deficiency induces NLRP3 inflammasome activation and autoinflammation of macrophages in a murine endolymphatic hydrops model

Zhang

Liu

et al. 2023

Nat Commun

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“…For example, as a key downstream effector of Ras, SGK1 increases glucose uptake via glucose transporter protein 1 (GLUT1), which promotes glucose-mediated carbon flux into multiple metabolic pathways to inhibit anoikis (Fig. 2 D) [ 65 , 66 ]. Ras also reduce the phosphatase PHLPP1 expression, which promotes anoikis by activating p38 MAPK (Fig.…”

Section: Effect Of Chronic Stress On Tumor Cellsmentioning

confidence: 99%

Chronic stress in solid tumor development: from mechanisms to interventions

et al. 2023

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Chronic stress results in disturbances of body hormones through the neuroendocrine system. Cancer patients often experience recurrent anxiety and restlessness during disease progression and treatment, which aggravates disease progression and hinders treatment effects. Recent studies have shown that chronic stress-regulated neuroendocrine systems secret hormones to activate many signaling pathways related to tumor development in tumor cells. The activated neuroendocrine system acts not only on tumor cells but also modulates the survival and metabolic changes of surrounding non-cancerous cells. Current clinical evidences also suggest that chronic stress affects the outcome of cancer treatment. However, in clinic, there is lack of effective treatment for chronic stress in cancer patients. In this review, we discuss the main mechanisms by which chronic stress regulates the tumor microenvironment, including functional regulation of tumor cells by stress hormones (stem cell-like properties, metastasis, angiogenesis, DNA damage accumulation, and apoptotic resistance), metabolic reprogramming and immune escape, and peritumor neuromodulation. Based on the current clinical treatment framework for cancer and chronic stress, we also summarize pharmacological and non-pharmacological therapeutic approaches to provide some directions for cancer therapy.

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“…Neoplastic cells preferentially uptake the tracer in 18 F-FDG-PET imaging [ 102 ]. Both GLUT1 mRNA expression and Glut1 protein translocation from the endomembranes to the cell surface are promoted by PI3K/AKt signaling [ 103 , 104 ]. Targeting Glut1 with anti-Glut1 antibodies in breast cancer lines caused an up-to-75% reduction in proliferation [ 105 ].…”

Section: Glut1 Inhibition In Other Settingsmentioning

confidence: 99%

One Molecule for Mental Nourishment and More: Glucose Transporter Type 1—Biology and Deficiency Syndrome

et al. 2022

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Glucose transporter type 1 (Glut1) is the main transporter involved in the cellular uptake of glucose into many tissues, and is highly expressed in the brain and in erythrocytes. Glut1 deficiency syndrome is caused mainly by mutations of the SLC2A1 gene, impairing passive glucose transport across the blood–brain barrier. All age groups, from infants to adults, may be affected, with age-specific symptoms. In its classic form, the syndrome presents as an early-onset drug-resistant metabolic epileptic encephalopathy with a complex movement disorder and developmental delay. In later-onset forms, complex motor disorder predominates, with dystonia, ataxia, chorea or spasticity, often triggered by fasting. Diagnosis is confirmed by hypoglycorrhachia (below 45 mg/dL) with normal blood glucose, 18F-fluorodeoxyglucose positron emission tomography, and genetic analysis showing pathogenic SLC2A1 variants. There are also ongoing positive studies on erythrocytes’ Glut1 surface expression using flow cytometry. The standard treatment still consists of ketogenic therapies supplying ketones as alternative brain fuel. Anaplerotic substances may provide alternative energy sources. Understanding the complex interactions of Glut1 with other tissues, its signaling function for brain angiogenesis and gliosis, and the complex regulation of glucose transportation, including compensatory mechanisms in different tissues, will hopefully advance therapy. Ongoing research for future interventions is focusing on small molecules to restore Glut1, metabolic stimulation, and SLC2A1 transfer strategies. Newborn screening, early identification and treatment could minimize the neurodevelopmental disease consequences. Furthermore, understanding Glut1 relative deficiency or inhibition in inflammation, neurodegenerative disorders, and viral infections including COVID-19 and other settings could provide clues for future therapeutic approaches.

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SGK1 signaling promotes glucose metabolism and survival in extracellular matrix detached cells

Cited by 39 publications

References 44 publications

Serum/glucocorticoid-inducible kinase 1 deficiency induces NLRP3 inflammasome activation and autoinflammation of macrophages in a murine endolymphatic hydrops model

Serum/glucocorticoid-inducible kinase 1 deficiency induces NLRP3 inflammasome activation and autoinflammation of macrophages in a murine endolymphatic hydrops model

Chronic stress in solid tumor development: from mechanisms to interventions

One Molecule for Mental Nourishment and More: Glucose Transporter Type 1—Biology and Deficiency Syndrome

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