Sodium/proton exchanger isoform 1 regulates intracellular pH and cell proliferation in human ovarian cancer

Cancer cells generate protons (H+) that are extruded to the extracellular medium mainly via the Na+/H+ exchanger 1 (NHE1), which regulates intracellular pH (pHi) and cell proliferation. In primary cultures of human ascites-derived ovarian cancer cells (haOC) we assayed whether NHE1 was required for...

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Published in:Biochimica et biophysica acta. Molecular basis of disease 2017-01, Vol.1863 (1), p.81-91
Main Authors: Sanhueza, Carlos, Araos, Joaquín, Naranjo, Luciano, Toledo, Fernando, Beltrán, Ana R, Ramírez, Marco A, Gutiérrez, Jaime, Pardo, Fabián, Leiva, Andrea, Sobrevia, Luis
Format: Article
Language:English
Subjects:
Cell Proliferation
Cells, Cultured
Female
Human
Humans
Hydrogen-Ion Concentration
NHE1
Ovarian cancer
Ovarian Neoplasms - metabolism
Ovarian Neoplasms - pathology
Ovary - metabolism
Ovary - pathology
pHi
Sodium-Hydrogen Exchanger 1 - analysis
Sodium-Hydrogen Exchanger 1 - metabolism
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Summary:Cancer cells generate protons (H+) that are extruded to the extracellular medium mainly via the Na+/H+ exchanger 1 (NHE1), which regulates intracellular pH (pHi) and cell proliferation. In primary cultures of human ascites-derived ovarian cancer cells (haOC) we assayed whether NHE1 was required for pHi modulation and cell proliferation. Human ovary expresses NHE1, which is higher in haOC and A2780 (ovarian cancer cells) compared with HOSE cells (normal ovarian cells). Basal pHi and pHi recovery (following a NH4Cl pulse) was higher in haOC and A2780, compared with HOSE cells. Zoniporide (NHE1 inhibitor) caused intracellular acidification and pHi recovery was independent of intracellular buffer capacity, but reduced in NHE1 knockdown A2780 cells. Zoniporide reduced the maximal proliferation capacity, cell number, thymidine incorporation, and ki67 (marker of proliferation) fluorescence in haOC cells. SLC9A1 (for NHE1) amplification associated with lower overall patient survival. In conclusion, NHE1 is expressed in human ovarian cancer where it has a pro-proliferative role. Increased NHE1 expression and activity constitute an unfavourable prognostic factor in these patients. •Human ovary tissue expresses functional Na+/H+ exchanger 1 (NHE1) isoform.•Expression of NHE1 is increased in human ovarian tumour epithelial cells.•NHE1 regulates intracellular pH in human ovarian tumour cells.•NHE1 activity is a pro-proliferative factor in human ovarian tumour cells.•High NHE1 expression and activity associate with lower overall patients' survival
ISSN:0925-4439
1879-260X
DOI:10.1016/j.bbadis.2016.10.013