ArticleNeoplasia (New York, N.Y.)2015
A novel NHE1-centered signaling cassette drives epidermal growth factor receptor-dependent pancreatic tumor metastasis and is a target for combination therapy.
Article in Neoplasia (New York, N.Y.), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 89 citations in OpenAlex.
- Microenvironmental acidosis drives PARP- and ATM inhibitor resistance in p53 deficient pancreatic cancer.iScience · 2026Article
- NHE1-Mediated Metabolic Reprogramming in Cancer.Metabolites · 2026Review
- Acid-base transporters in the context of tumor heterogeneity.Pflugers Archiv : European journal of physiology · 2024Review
- Review
- Acid-base homeostasis orchestrated by NHE1 defines the pancreatic stellate cell phenotype in pancreatic cancer.JCI insight · 2023Article
- IDH1 K224 acetylation promotes colorectal cancer via miR-9-5p/NHE1 axis-mediated regulation of acidic microenvironment.iScience · 2023Article
- ECM Composition Differentially Regulates Intracellular and Extracellular pH in Normal and Cancer Pancreatic Duct Epithelial Cells.International journal of molecular sciences · 2023Article
- Comprehensive DNA Methylation Analysis Indicates That Pancreatic Intraepithelial Neoplasia Lesions Are Acinar-Derived and Epigenetically Primed for Carcinogenesis.Cancer research · 2023Article
- Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness.International journal of cancer · 2023Article
- Inhibition of Na+/H+ exchanger (NHE) 7 by 5-(N-ethyl-N-isopropyl)-Amiloride displays anti-cancer activity in non-small cell lung cancer by disrupting cancer stem cell activity and downregulating PD-L1 expression.American journal of cancer research · 2023Article
- Targeting Na-H exchanger 1 overcomes nuclear factor kappa B-mediated tumor resistance to radiotherapy.Neoplasia (New York, N.Y.) · 2023Article
- Structural informatic study of determined and AlphaFold2 predicted molecular structures of 13 human solute carrier transporters and their water-soluble QTY variants.Scientific reports · 2022Article
- Cancer Associated Fibroblast (CAF) Regulation of PDAC Parenchymal (CPC) and CSC Phenotypes Is Modulated by ECM Composition.Cancers · 2022Article
- Proton export upregulates aerobic glycolysis.BMC biology · 2022Article
- Combinatorial Therapy of Cancer: Possible Advantages of Involving Modulators of Ionic Mechanisms.Cancers · 2022Review
- Permissive role of NaMolecular and cellular biochemistry · 2022Article
- Ion Transporting Proteins and Cancer: Progress and Perspectives.Reviews of physiology, biochemistry and pharmacology · 2022Article
- Targeting the Interplay between Cancer Metabolic Reprogramming and Cell Death Pathways as a Viable Therapeutic Path.Biomedicines · 2021Review
- The Interplay between Dysregulated Ion Transport and Mitochondrial Architecture as a Dangerous Liaison in Cancer.International journal of molecular sciences · 2021Review
- Advances in research on the regulatory mechanism of NHE1 in tumors.Oncology letters · 2021Review
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers principally because of early invasion and metastasis. The epidermal growth factor receptor (EGFR) is essential for PDAC development even in the presence of Kras, but its inhibition with erlotinib gives only a modest clinical response, making the discovery of novel EGFR targets of critical interest. Here, we revealed by mining a human pancreatic gene expression database that the metastasis promoter Na(+)/H(+) exchanger (NHE1) associates with the EGFR in PDAC. In human PDAC cell lines, we confirmed that NHE1 drives both basal and EGF-stimulated three-dimensional growth and early invasion via invadopodial extracellular matrix digestion. EGF promoted the complexing of EGFR with NHE1 via the scaffolding protein Na+/H+ exchanger regulatory factor 1, engaging EGFR in a negative transregulatory loop that controls the extent and duration of EGFR oncogenic signaling and stimulates NHE1. The specificity of NHE1 for growth or invasion depends on the segregation of the transient EGFR/Na+/H+ exchanger regulatory factor 1/NHE1 signaling complex into dimeric subcomplexes in different lipid raftlike membrane domains. This signaling complex was also found in tumors developed in orthotopic mice. Importantly, the specific NHE1 inhibitor cariporide reduced both three-dimensional growth and invasion independently of PDAC subtype and synergistically sensitized these behaviors to low doses of erlotinib.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.