The Na+/H+ Exchanger Controls Deoxycholic Acid-Induced Apoptosis by a H+-Activated, Na+-Dependent Ionic Shift in Esophageal Cells
| Autor: | Katerina Dvorak, Aaron Goldman, Kimberly A. Hill, Mohammad Shahidullah, Nicholas A. Delamere, Amritlal Mandal, Hwu Dau Rw Chen, Mohammad R. Khan, Heather B. Roesly |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Anatomy and Physiology
Tumor Physiology lcsh:Medicine Apoptosis Antiport Proteins Biochemistry Ion Channels Ouabain Transmembrane Transport Proteins chemistry.chemical_compound 0302 clinical medicine Molecular Cell Biology Basic Cancer Research Homeostasis lcsh:Science Cells Cultured Gastrointestinal Neoplasms 0303 health sciences Multidisciplinary Cell Death Bile acid Chemistry Deoxycholic acid Hydrogen-Ion Concentration Oncology 030220 oncology & carcinogenesis Medicine Intracellular Research Article Deoxycholic Acid medicine.drug Programmed cell death Sodium-Hydrogen Exchangers medicine.drug_class Caspase 3 Bile Acids and Salts 03 medical and health sciences Esophagus Cations Chemical Biology medicine Humans Biology 030304 developmental biology Plasma Proteins lcsh:R Sodium Proteins Molecular biology Sodium–hydrogen antiporter lcsh:Q Physiological Processes Lysosomes Hydrogen |
| Zdroj: | PLoS ONE PLoS ONE, Vol 6, Iss 8, p e23835 (2011) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0023835 |
| Popis: | Apoptosis resistance is a hallmark of cancer cells. Typically, bile acids induce apoptosis. However during gastrointestinal (GI) tumorigenesis the cancer cells develop resistance to bile acid-induced cell death. To understand how bile acids induce apoptosis resistance we first need to identify the molecular pathways that initiate apoptosis in response to bile acid exposure. In this study we examined the mechanism of deoxycholic acid (DCA)-induced apoptosis, specifically the role of Na(+)/H(+) exchanger (NHE) and Na(+) influx in esophageal cells. In vitro studies revealed that the exposure of esophageal cells (JH-EsoAd1, CP-A) to DCA (0.2 mM-0.5 mM) caused lysosomal membrane perturbation and transient cytoplasmic acidification. Fluorescence microscopy in conjunction with atomic absorption spectrophotometry demonstrated that this effect on lysosomes correlated with influx of Na(+), subsequent loss of intracellular K(+), an increase of Ca(2+) and apoptosis. However, ethylisopropyl-amiloride (EIPA), a selective inhibitor of NHE, prevented Na(+), K(+) and Ca(2+) changes and caspase 3/7 activation induced by DCA. Ouabain and amphotericin B, two drugs that increase intracellular Na(+) levels, induced similar changes as DCA (ion imbalance, caspase3/7 activation). On the contrary, DCA-induced cell death was inhibited by medium with low a Na(+) concentrations. In the same experiments, we exposed rat ileum ex-vivo to DCA with or without EIPA. Severe tissue damage and caspase-3 activation was observed after DCA treatment, but EIPA almost fully prevented this response. In summary, NHE-mediated Na(+) influx is a critical step leading to DCA-induced apoptosis. Cells tolerate acidification but evade DCA-induced apoptosis if NHE is inhibited. Our data suggests that suppression of NHE by endogenous or exogenous inhibitors may lead to apoptosis resistance during GI tumorigenesis. |
| Databáze: | OpenAIRE |
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