Hypertonic Saline Attenuates Colonic Tumor Cell Metastatic Potential by Activating Transmembrane Sodium Conductance |
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Authors: | Conor J Shields Desmond C Winter John P Geibel Gerald C O’Sullivan Jiang Huai Wang H Paul Redmond |
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Institution: | (1) Department of Surgery, National University of Ireland, Cork, Ireland;(2) Department of Surgery, Yale University, New Haven, Connecticut, USA;(3) Department of Cellular and Molecular Physiology, Yale University, New Haven, Connecticut, USA |
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Abstract: | Hypertonic saline (HTS) suppresses tumor cell-endothelial interactions by reducing integrin expression. This translates into
reduced adhesion, migration and metastatic potential. This study determined the relative contributions of hyperosmolarity
and sodium-specific hypertonicity on the inhibitory effects of HTS, the intracellular pH and sodium responses to HTS and the
role of cytoskeletal remodeling in these changes. Human colonic tumor cells (LS174T) were exposed to lipopolysaccharide under
isotonic, hypertonic, sodium-free (N-methyl- D-glucamine), hyperosmolar (mannitol or urea), disrupted cytoskeletal (10 μg/ml cytochalasin D) conditions or in the presence
of 5-(N-ethyl-N-isopropyl)amiloride (EIPA). β1 integrin expression was measured flow-cytometrically. Intracellular sodium and pH were measured with confocal laser microscopic
imaging. Statistical analysis was performed with analysis of variance, and P < 0.05 was considered significant. Data are represented as mean ± SEM. Hypertonic exposure attenuated integrin expression (62.03 ± 4.7% of control, P < 0.04). No discernible effect was observed with sodium-free or hyperosmolar solutions. HTS evoked a cellular alkalinization
(by a mean 0.2 pH units) and an increase in cytosolic sodium concentration (by a mean 12.4 mM, P < 0.001) via upregulation of sodium-hydrogen exchange. Disassembly of actin microfilaments by cytochalasin D and antiporter
inhibition with EIPA abrogated the effect of hypertonicity on integrin expression and intracellular sodium and pH (P < 0.05). HTS downregulates adhesion molecule expression via a hypertonic, sodium-specific, cytoskeletally mediated mechanism
that involves activation of sodium-hydrogen exchange with associated changes in intracellular pH and sodium concentrations. |
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Keywords: | Hypertonic saline Colonic tumor cell Metastasis Transmembrane sodium conductance |
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