ArticleOncotarget2016
Na+/H+ exchanger NHE1 regulation modulates metastatic potential and epithelial-mesenchymal transition of triple-negative breast cancer cells.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 63 citations in OpenAlex.
- NHE1-Mediated Metabolic Reprogramming in Cancer.Metabolites · 2026Review
- Intracellular pH regulates β-catenin with low pHi increasing adhesion and signaling functions.The Journal of biological chemistry · 2026Article
- A system-wide investigation into the phosphoregulatory network of TNIK and its cellular implications.Frontiers in bioinformatics · 2026Article
- A role for pH dynamics regulating transcription factor DNA-binding selectivity.Nucleic acids research · 2025Article
- Intracellular pH differentially regulates transcription of metabolic and signaling pathways in normal epithelial cells.The Journal of biological chemistry · 2024Article
- Intracellular pH dynamics regulates intestinal stem cell lineage specification.Nature communications · 2023Article
- Intracellular pH affects mitochondrial homeostasis in cultured human corneal endothelial cells prepared for cell injection therapy.Scientific reports · 2022Article
- Permissive role of NaMolecular and cellular biochemistry · 2022Article
- Colorectal cancer extracellular acidosis decreases immune cell killing and is partially ameliorated by pH-modulating agents that modify tumor cell cytokine profiles.American journal of cancer research · 2022Article
- Role of pH Regulatory Proteins and Dysregulation of pH in Prostate Cancer.Reviews of physiology, biochemistry and pharmacology · 2022Article
- Roles of the NaInternational journal of molecular sciences · 2021Article
- Amino Acids 785, 787 of the NaInternational journal of molecular sciences · 2021Article
- Dynamic NaeLife · 2021Article
- Role of Genetic Mutations of the NaMolecular and cellular biochemistry · 2021Review
- Influence of nNav1.5 on MHC class I expression in breast cancer.Journal of biosciences · 2021Article
- Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New HInternational journal of molecular sciences · 2020Review
- The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis.International journal of molecular sciences · 2020Review
- Intracellular pH Regulates Cancer and Stem Cell Behaviors: A Protein Dynamics Perspective.Frontiers in oncology · 2020Review
- Cancer Cell enters reversible quiescence through Intracellular Acidification to resist Paclitaxel Cytotoxicity.International journal of medical sciences · 2020Article
- Electrochemical patterns during Drosophila oogenesis: ion-transport mechanisms generate stage-specific gradients of pH and membrane potential in the follicle-cell epithelium.BMC developmental biology · 2019Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In triple-negative breast cancer (TNBC), the high recurrence rate, increased invasion and aggressive metastatic formation dictate patient survival. We previously demonstrated a critical role for the Na+/H+ exchanger isoform 1 (NHE1) in controlling metastasis of triple-negative cells. Here, we investigated the effect of changes to three regulatory loci of NHE1. Two via the Ras/Raf/ERK/p90RSK pathway: p90RSK/14-3-3 (S703A) and ERK1/2 (S766,770,771A, SSSA) and a third via a calmodulin-binding domain (K641,R643,645,647E, 1K3R4E). MDA-MB-231 cells with a mutation at the p90RSK site (S703A-NHE1) changed from a wild-type mesenchymal morphology to a smaller epithelial-like phenotype with a loss of expression of mesenchymal marker vimentin. S703A cells also had reduced metastatic potential and markedly decreased rates of migration, invasion, spheroid growth, anchorage-dependent and soft agar colony formation. Similarly, BI-D1870, a specific inhibitor of p90RSK, significantly inhibited the metastatic potential of highly invasive MDA-MB-231 and moderately invasive MDA-MB-468 TNBC cells, but was minimally effective in non-invasive Hs578T TNBC cells. In contrast, invasion and spheroid growth were unaffected in cells containing NHE1 with mutations interfering with its activation by ERK1/2 (SSSA), though rates of migration and colony formation were reduced. Cells with a constitutive activation of NHE1 via the 1K3R4E mutation exhibited higher rates of migration, invasion, and spheroid growth. Taken together, our data demonstrate the critical role of NHE1 in metastasis, and suggest a novel link between NHE1 and the expression and cytosolic organization of vimentin, a key factor in epithelial-mesenchymal transition, that is dependent on p90RSK/14-3-3-mediated activation of the exchanger.
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