Down-Regulation of the Na+,Cl- Coupled Creatine Transporter CreaT (SLC6A8) by Glycogen Synthase Kinase GSK3ß

Fezai, Myriam; Jèmaà, Mohamed; Fakhri, Hajar; Chen, Hong; Elsir, Bhaeldin; Pelzl, Lisann; Läng, Florian

doi:10.1159/000453177

Cited by 5 publications

(3 citation statements)

References 59 publications

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“…The creatine transporter solute carrier family 6 member 8 (SLC6A8) is encoded by an 8.4-kb gene (7) and belongs to the subfamily of GABA transporters (8). SLC6A8 is a member of the sodium-and chloride-coupled transporter superfamily of neurotransmitters and organic permeants and is expressed in a variety of tissues, including brain, retina, skeletal muscle, and heart as well as a variety of epithelial cells (9). Heinbockel et al reported that SLC6A8 is expressed in the bronchus, macrophages, and capillaries of chronic obstructive pulmonary disease (COPD) patients (10).…”

Section: Original Articlementioning

confidence: 99%

SLC6A8 is involved in the progression of non-small cell lung cancer through the Notch signaling pathway

2021

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Background: Solute carrier family 6 member 8 (SLC6A8) is known to be involved in the development of human tumors; however, the effect of SLC6A8 on the growth of non-small cell lung cancer (NSCLC) remains unclear. Here, we explored the role and potential action mechanism of SLC6A8 in NSCLC. Methods:We used public databases [Oncomine, Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA)] to explore the expression of SLC6A8 in NSCLC. Additionally, we used immunohistochemistry to detect the expression of SLC6A8 in NSCLC clinicopathological tissues (cancer and adjacent tissues) and Western blotting to detect the expression of SLC6A8 in NSCLC clinicopathological tissues, NSCLC cell lines (A549, H1299, H520, and H1975), and a normal epithelial cell line (BEAS-2B). Using overexpression and knockdown of the SLC6A8 gene, we analyzed the in vitro effects of SLC6A8 on the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of NSCLC and also the possible molecular mechanism with Notch signaling pathway.Results: Bioinformatic analysis demonstrated that SLC6A8 is highly expressed in NSCLC and is related to poor prognosis. We found that the expression of the SLC6A8 protein in human lung cancer tissues was significantly higher than that in adjacent tissues. In addition, it was also significantly higher in lung cancer cell lines (A549, H1299, H520, and H1975) than that in normal lung epithelium-BEAS-2B. Moreover, SLC6A8 overexpression promotes the proliferation, migration and invasion in vitro in NSCLC, accompanied by the activation of notch signaling pathway and the up-regulation of MMP9 and E-cadherin proteins.Knocking down SLC6A8 can inhibit the above effects on cells.Conclusions: SLC6A8 promotes the malignant progression of NSCLC and activates the Notch signaling pathway. Therefore, SLC6A8 is expected to become a molecular target for NSCLC treatment.

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Section: Original Articlementioning

confidence: 99%

SLC6A8 is involved in the progression of non-small cell lung cancer through the Notch signaling pathway

2021

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“…Here, we showed that SLC6A8 was highly expressed in activated CD8+ T cells and that leukaemia‐derived sEV‐related miR‐19a‐3p directly inhibited SLC6A8 expression in CD8+ T cells. Previous findings have suggested that SLC6A8 activity/expression may be regulated by extracellular and cytosolic creatine levels (Alfieri et al., 2006 ), hormones (Omerovic et al., 2003 ), and kinase activity (such as AMP‐activated kinase and glycogen synthase kinase) (Darrabie et al., 2011 ; Fezai et al., 2016 ). Herein, we revealed that miR‐19a‐3p directly inhibited SLC6A8 expression at the transcriptional level.…”

Section: Discussionmentioning

confidence: 99%

Tumour‐derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8‐mediated creatine import in NPM1‐mutated acute myeloid leukaemia

Peng

Ren

Jing

et al. 2021

J of Extracellular Vesicle

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Acute myeloid leukaemia (AML) carrying nucleophosmin (NPM1) mutations has been defined as a distinct entity of acute leukaemia. Despite remarkable improvements in diagnosis and treatment, the long‐term outcomes for this entity remain unsatisfactory. Emerging evidence suggests that leukaemia, similar to other malignant diseases, employs various mechanisms to evade killing by immune cells. However, the mechanism of immune escape in NPM1‐mutated AML remains unknown. In this study, both serum and leukemic cells from patients with NPM1‐mutated AML impaired the immune function of CD8+ T cells in a co‐culture system. Mechanistically, leukemic cells secreted miR‐19a‐3p into the tumour microenvironment (TME) via small extracellular vesicles (sEVs), which was controlled by the NPM1‐mutated protein/CCCTC‐binding factor (CTCF)/poly (A)‐binding protein cytoplasmic 1 (PABPC1) signalling axis. sEV‐related miR‐19a‐3p was internalized by CD8+ T cells and directly repressed the expression of solute‐carrier family 6 member 8 (SLC6A8; a creatine‐specific transporter) to inhibit creatine import. Decreased creatine levels can reduce ATP production and impair CD8+ T cell immune function, leading to immune escape by leukemic cells. In summary, leukemic cell‐derived sEV‐related miR‐19a‐3p confers immunosuppression to CD8+ T cells by targeting SLC6A8‐mediated creatine import, indicating that sEV‐related miR‐19a‐3p might be a promising therapeutic target for NPM1‐mutated AML.

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“…Mechanisms involved in the neuroprotective effect of lithium include direct or Akt-mediated inhibition of glycogen synthase kinase GSK-3β, Akt-mediated inhibition of the proapoptotic forkhead box class O transcription factor Foxo3a and murine double minute (MDM), induction of autophagy by inhibition of inositol monophosphatase, stimulation of production and activity of neuroprotective brain derived neurotrophic factor BDNF, up-regulation of anti-apoptotic protein Bcl-2, as well as down-regulation of pro-apoptotic transcription factor p53, of the pro-apoptotic proteins Bad and Bax, of glutamate excitotoxicity, of calpain and of oxidative stress [12, 81, 84]. By inhibiting glycogen synthase kinase GSK3β,lithium may modify the activity of carriers [85, 86] and channels [86]. Moreover, lithium may inhibit toll-like receptor TLR4 expression in astrocytes and thus counteract inflammation [87].…”

Section: Autophagy and Cell Survivalmentioning

confidence: 99%

Neurons, Erythrocytes and Beyond –The Diverse Functions of Chorein

et al. 2017

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Chorea-acanthocytosis (ChAc), a neurodegenerative disease, results from loss-of-function-mutations of the chorein-encoding gene VPS13A. Affected patients suffer from a progressive movement disorder including chorea, parkinsonism, dystonia, tongue protrusion, dysarthria, dysphagia, tongue and lip biting, gait impairment, progressive distal muscle wasting, weakness, epileptic seizures, cognitive impairment, and behavioral changes. Those pathologies may be paralleled by erythrocyte acanthocytosis. Chorein supports activation of phosphoinositide-3-kinase (PI3K)-p85-subunit with subsequent up-regulation of ras-related C3 botulinum toxin substrate 1 (Rac1) activity, p21 protein-activated kinase 1 (PAK1) phosphorylation, and activation of several tyrosine kinases. Chorein sensitive PI3K signaling further leads to stimulation of the serum and glucocorticoid inducible kinase SGK1, which in turn upregulates ORAI1, a Ca²⁺-channel accomplishing store operated Ca²⁺-entry (SOCE). The signaling participates in the regulation of cytoskeletal architecture on the one side and cell survival on the other. Compromised cytoskeletal architecture has been shown in chorein deficient erythrocytes, fibroblasts and endothelial cells. Impaired degranulation was observed in chorein deficient PC12 cells and in platelets from ChAc patients. Similarly, decreased ORAI1 expression and SOCE as well as compromised cell survival were seen in fibroblasts and neurons isolated from ChAc patients. ORAI1 expression, SOCE and cell survival can be restored by lithium treatment, an effect disrupted by pharmacological inhibition of SGK1 or ORAI1. Chorein, SGK1, ORAI1 and SOCE further confer survival of tumor cells. In conclusion, much has been learned about the function of chorein and the molecular pathophysiology of chorea-acanthocytosis. Most importantly, a treatment halting or delaying the clinical course of this devastating disease may become available. A controlled clinical study is warranted, in order to explore whether the in vitro observations indeed reflect the in vivo pathology of the disease.

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Down-Regulation of the Na+,Cl- Coupled Creatine Transporter CreaT (SLC6A8) by Glycogen Synthase Kinase GSK3ß

Cited by 5 publications

References 59 publications

SLC6A8 is involved in the progression of non-small cell lung cancer through the Notch signaling pathway

SLC6A8 is involved in the progression of non-small cell lung cancer through the Notch signaling pathway

Tumour‐derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8‐mediated creatine import in NPM1‐mutated acute myeloid leukaemia

Neurons, Erythrocytes and Beyond –The Diverse Functions of Chorein

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