ArticleMolecular cancer2014
WNK1-OSR1 kinase-mediated phospho-activation of Na+-K+-2Cl- cotransporter facilitates glioma migration.
Article in Molecular cancer, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 102 citations in OpenAlex.
- Synthesis of new sulfoximines and sulfonimidamides derivatives as NKCC1 inhibitors.Frontiers in chemistry · 2026Article
- WNK1 promotes head and neck squamous cell carcinoma progression through activation of NF-κB signaling pathway.Discover oncology · 2025Article
- Connexin 43 drives glioblastoma cancer stem cell phenotypes through a WNK lysine-deficient protein kinase 1-c-MYC signaling axis.Cell reports · 2025Article
- The Omega-3 Fatty Acids Eicosapentaenoic Acid and Docosahexaenoic Acid Enhance the Effects of Temozolomide Chemotherapy in Glioblastoma Cells.International journal of molecular sciences · 2025Article
- Comparison of the Effect of the Combination of Sodium Valproate and Sodium Dichloroacetate on the Expression ofPharmaceutics · 2025Article
- In Vivo and In Vitro Experimental Study Comparing the Effect of a Combination of Sodium Dichloroacetate and Valproic Acid with That of Temozolomide on Adult Glioblastoma.International journal of molecular sciences · 2025Article
- Article
- Identification and validation of DNA methylation-driven gene OSR1 as a novel tumor suppressor for the diagnosis and prognosis of breast cancer.Frontiers in genetics · 2025Article
- Bioinformatics analysis identifies WNK1 gene as a potential biomarker for cholangiocarcinoma diagnosis and immune infiltration.Journal, genetic engineering & biotechnology · 2024Article
- A New Phase for WNK Kinase Signaling Complexes as Biomolecular Condensates.Physiology (Bethesda, Md.) · 2024Review
- Differential Impact of Valproic Acid onBiomedicines · 2024Article
- Unveiling the therapeutic potential of IHMT-337 in glioma treatment: targeting the EZH2-SLC12A5 axis.Molecular medicine (Cambridge, Mass.) · 2024Article
- Dihydrotestosterone Augments the Angiogenic and Migratory Potential of Human Endothelial Progenitor Cells by an Androgen Receptor-Dependent Mechanism.International journal of molecular sciences · 2024Article
- Inhibition of WNK Kinases in NK Cells Disrupts Cellular Osmoregulation and Control of Tumor Metastasis.Journal of innate immunity · 2024Article
- T cell migration requires ion and water influx to regulate actin polymerization.Nature communications · 2023Article
- Regulatory role of PI3K/Akt/WNK1 signal pathway in mouse model of bone cancer pain.Scientific reports · 2023Article
- B cell-intrinsic requirement for WNK1 kinase in antibody responses in mice.The Journal of experimental medicine · 2023Article
- ORAI Calcium Channels: Regulation, Function, Pharmacology, and Therapeutic Targets.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Identification of a Class of WNK Isoform-Specific Inhibitors Through High-Throughput Screening.Drug design, development and therapy · 2023Article
- WNK3 inhibition elicits antitumor immunity by suppressing PD-L1 expression on tumor cells and activating T-cell function.Experimental & molecular medicine · 2022Article
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundThe bumetanide (BMT)-sensitive Na+-K+-2Cl- cotransporter isoform 1 (NKCC1) maintains cell volume homeostasis by increasing intracellular K+ and Cl- content via regulatory volume increase (RVI). Expression levels of NKCC1 positively correlate with the histological grade and severity of gliomas, the most common primary adult brain tumors, and up-regulated NKCC1 activity facilitates glioma cell migration and apoptotic resistance to the chemotherapeutic drug temozolomide (TMZ). However, the cellular mechanisms underlying NKCC1 functional up-regulation in glioma and in response to TMZ administration remain unknown.
methodsExpression of NKCC1 and its upstream kinases With-No-K (Lysine) kinase 1 (WNK1) and oxidative stress-responsive kinase-1 (OSR1) in different human glioma cell lines and glioma specimens were detected by western blotting and immunostaining. Live cell imaging and microchemotaxis assay were applied to record glioma cell movements under different treatment conditions. Fluorescence indicators were utilized to measure cell volume, intracellular K+ and Cl- content to reflect the activity of NKCC1 on ion transportation. Small interfering RNA (siRNA)-mediated knockdown of WNK1 or OSR1 was used to explore their roles in regulation of NKCC1 activity in glioma cells. Results of different treatment groups were compared by one-way ANOVA using the Bonferroni post-hoc test in the case of multiple comparisons.
resultsWe show that compared to human neural stem cells and astrocytes, human glioma cells exhibit robust increases in the activation and phosphorylation of NKCC1 and its two upstream regulatory kinases, WNK1 and OSR1. siRNA-mediated knockdown of WNK1 or OSR1 reduces intracellular K+ and Cl- content and RVI in glioma cells by abolishing NKCC1 regulatory phospho-activation. Unexpectedly, TMZ activates the WNK1/OSR1/NKCC1 signaling pathway and enhances glioma migration. Pharmacological inhibition of NKCC1 with its potent inhibitor BMT or siRNA knockdown of WNK1 or OSR1 significantly decreases glioma cell migration after TMZ treatment.
conclusionTogether, our data show a novel role for the WNK1/OSR1/NKCC1 pathway in basal and TMZ-induced glioma migration, and suggest that glioma treatment with TMZ might be improved by drugs that inhibit elements of the WNK1/OSR1/NKCC1 signaling pathway.
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