The sodium/myo-inositol co-transporter SLC5A3 promotes non-small cell lung cancer cell growth

Cui, Zihan; Mu, Chuanyong; Wu, Zhichao; Pan, Shu; Cheng, Zewen; Zhang, Zhi-qing; Zhao, Jun; Xu, Chun Yan

doi:10.1038/s41419-022-05017-y

Cited by 9 publications

(8 citation statements)

References 50 publications

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“…49,50 This is consistent with our recent work demonstrating an increased number of BCAM hi basal cells in CRSwNP. 19 Finally, basal cells from CRSwNP also had high levels of expression of genes involved in metabolism including SLC5A3 , encoding a sodium and myo-inositol co-transporter that activates cell proliferation through an Akt/mTOR pathway, 51 and SLC2A1 , encoding the glucose transporter GLUT1 that is upstream of the glycolysis pathway. 52,53 Over-representation analysis of the 188 DEGs with higher expression in CRSwNP basal EpCs yielded GO biological processes gene sets involved in wound healing (padj=0.028) and secreted peptidase inhibitors (padj=0.0061) ( Fig 1D ), perhaps consistent with DEGs involved in barrier function, stemness, and growth.…”

Section: Resultsmentioning

confidence: 99%

Section: Data Availabilitymentioning

confidence: 99%

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Increased epithelial mTORC1 activity in chronic rhinosinusitis with nasal polyps

Huang,

Hallen,

Lee

et al. 2023

Preprint

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Background: The airway epithelium plays a central role in the pathogenesis of chronic respiratory diseases such as asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), but the mechanisms by which airway epithelial cells (EpCs) maintain inflammation are poorly understood. Objective: We hypothesized that transcriptomic assessment of sorted airway EpCs across the spectrum of differentiation would allow us to define mechanisms by which EpCs perpetuate airway inflammation. Methods: Ethmoid sinus EpCs from adult patients with CRS were sorted into 3 subsets, bulk RNA sequenced, and analyzed for differentially expressed genes and pathways. Single cell RNA-seq (scRNA-seq) datasets from eosinophilic and non-eosinophilic CRSwNP and bulk RNA-seq of EpCs from mild/moderate and severe asthma were assessed. Immunofluorescent staining and ex vivo functional analysis of sinus EpCs were used to validate our findings. Results: Analysis within and across purified EpC subsets revealed an enrichment in glycolytic programming in CRSwNP vs CRSsNP. Correlation analysis identified mammalian target of rapamycin complex 1 (mTORC1) as a potential regulator of the glycolytic program and identified EpC expression of cytokines and wound healing genes as potential sequelae. mTORC1 activity was upregulated in CRSwNP, and ex vivo inhibition demonstrated that mTOR is critical for EpC generation of CXCL8, IL-33, and CXCL2. Across patient samples, the degree of glycolytic activity was associated with T2 inflammation in CRSwNP, and with both T2 and non-T2 inflammation in severe asthma. Conclusions: Together, these findings highlight a metabolic axis required to support epithelial generation of cytokines critical to both chronic T2 and non-T2 inflammation in CRSwNP and asthma.

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Section: Resultsmentioning

confidence: 99%

Section: Data Availabilitymentioning

confidence: 99%

Increased epithelial mTORC1 activity in chronic rhinosinusitis with nasal polyps

Huang,

Hallen,

Lee

et al. 2023

Preprint

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“…The latter is highly expressed in various aggressive cancers 58 and biotin, one of its substrates 59 , has already been directly shown to influence proliferation of choriocarcinoma cells 60 . Comparably, SMIT has been reported to be an important driver of acute myeloid leukemia cell proliferation 61 and pharmacological inhibition with phlorizin, the substance DAPA and EMPA are derived from, led to reduced proliferation and migration of lung cancer cells 62 . Based on the described reduction in effect size of SGLT2is on HCF proliferation upon respective KD, we conclude that anti-fibrotic cardiovascular effects of SGLT2is 63–65 are mediated through their direct binding and inhibition of SMIT, SMVT, and NHE1.…”

Section: Discussionmentioning

confidence: 99%

SGLT2 inhibitors attenuate endothelial to mesenchymal transition and cardiac fibroblast activation

Schmidt,

Groß

et al. 2023

Preprint

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Beneficial effects of sodium glucose co-transporter 2 inhibitors (SGLT2is) in cardiovascular diseases have been extensively reported leading to the inclusion of these drugs in the treatment guidelines for heart failure. However, molecular actions especially on non-myocyte cells remain uncertain. We observed dose-dependent inhibitory effects of two SGLT2is, dapagliflozin (DAPA) and empagliflozin (EMPA), on inflammatory signaling in human umbilical vein endothelial cells (HUVECs). Proteomics analyses and subsequent enrichment analyses discovered profound effects of these SGLT2is on proteins involved in mitochondrial respiration and actin cytoskeleton. Validation in functional oxygen consumption measurements as well as tube formation and migration assays revealed strong impacts of DAPA. Considering that most influenced parameters played central roles in endothelial to mesenchymal transition (EndMT), we performedin vitroEndMT assays and identified substantial reduction of mesenchymal and fibrosis marker expression as well as changes in cellular morphology upon treatment with SGLT2is. In line, human cardiac fibroblasts (HCFs) exposed to DAPA showed less proliferation, reduced ATP production, and decelerated migration capacity while less extensive impacts were observed upon EMPA. Mechanistically, sodium proton exchanger 1 (NHE1) as well as sodium-myoinositol cotransporter (SMIT) and sodium-multivitamin cotransporter (SMVT) could be identified as relevant targets of SGLT2is in non-myocyte cardiovascular cells as validated by individual siRNA-knockdown experiments. In summary, we found comprehensive beneficial effects of SGLT2is on human endothelial cells and cardiac fibroblasts. The results of this study therefore support a distinct effect of selected SGLT2i on non-myocyte cardiovascular cells and grant further insights into potential molecular mode of action of these drugs.

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“…CCK-8, puromycin, cell culture medium, serum, MI, N-Acetyl-L-cysteine (NAC) as well as RNA reagents, fluorescence dyes, antibodies and the caspase inhibitors were provided by Dr. Cui 17 or purchased from Sigma (St. Louis, Mo).…”

Section: Methodsmentioning

confidence: 99%

“…CCK-8 viability assay, Trypan blue staining of cell death, Caspase-3 activity detection, “Transwell” assay of cell migration, nuclear EdU staining (quantifying cell proliferation), nuclear TUNEL staining of cell death, thiobarbituric acid reactive substance (TBAR) assay, CellROX staining assay of ROS (reactive oxygen species) production and mitochondrial depolarization (JC-1 staining) were reported in other studies 23 . qRT-PCR and Western blotting protocols were reported early 17 . mRNA primers for SLC5A3 and SLC5A11 were described early 24 , 25 .…”

Section: Methodsmentioning

confidence: 99%

SLC5A3 is important for cervical cancer cell growth

Li¹,

Shen²,

Cheng³

et al. 2023

Int. J. Biol. Sci.

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Novel molecular targets for cervical cancer must be identified. This study examined the role of SLC5A3, a myo-inositol transporter, in the pathogenesis of cervical cancer. Through boinformatics analysis, we showed that the SLC5A3 mRNA levels were upregulated in cervical cancer tissues. The upregulated SLC5A3 mRNA levels were negatively correlated with survival and progression-free interval. Genes co-expressed with SLC5A3 were enriched in multiple signaling cascades involved in cancer progression. In primary/established cervical cancer cells, SLC5A3 shRNA/knockout (KO) exerted growth-inhibitory effects and promoted cell death/apoptosis. Furthermore, SLC5A3 knockdown or KO downregulated myo-inositol levels, induced oxidative injury, and decreased Akt-mTOR activation in cervical cancer cells. In contrast, supplementation of myo-inositol or n-acetyl-L-cysteine or transduction of a constitutively active Akt1 construct mitigated SLC5A3 KO-induced cytotoxicity in cervical cancer cells. Lentiviral SLC5A3 overexpression construct transduction upregulated the cellular myo-inositol level and promoted Akt-mTOR activation, enhancing cervical cancer cell proliferation and migration. The binding of TonEBP to the SLC5A3 promoter was upregulated in cervical cancer. In vivo studies showed that intratumoral injection of SLC5A3 shRNA-expressing virus arrested cervical cancer xenograft growth in mice. SLC5A3 KO also inhibited pCCa-1 cervical cancer xenograft growth. The SLC5A3-depleted xenograft tissues exhibited myo-inositol downregulation, Akt-mTOR inactivation, and oxidative injury. Transduction of sh-TonEBP AAV construct downregulated SLC5A3 expression and inhibited pCCa-1 cervical cancer xenograft growth. Together, overexpressed SLC5A3 promotes growth of cervical cancer cells, representing as a novel therapeutic oncotarget for the devastating disease.

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The sodium/myo-inositol co-transporter SLC5A3 promotes non-small cell lung cancer cell growth

Cited by 9 publications

References 50 publications

Increased epithelial mTORC1 activity in chronic rhinosinusitis with nasal polyps

Increased epithelial mTORC1 activity in chronic rhinosinusitis with nasal polyps

SGLT2 inhibitors attenuate endothelial to mesenchymal transition and cardiac fibroblast activation

SLC5A3 is important for cervical cancer cell growth

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