Hypoxia Induced Downregulation of Na+/H+ Exchanger-1 Activity Decreases Tumor Cell Proliferation
Abstract
Objectives: Hypoxia and acidosis are the hallmarks of proliferative tumor microenvironment which can modulate the expression and function of
Na+/H+ exchanger-1 (NHE1) via hypoxia inducible factor 1 (Hif). Here, we investigate the severity and time dependent effects of chronic hypoxia on
NHE1 activity and its correlation with cell proliferation in mouse atrium tumor derived HL-1 cells.
Materials and Methods: NHE1 activity was recorded using intracellular pH (pHi) sensitive dye cSNARF-1 (Leica SP5). Cell proliferation was assessed
by live cell movie analyzer (Nanoentek, JuLI Br®) or immunofluorescence method.
Results: According to our results, mild chronic hypoxia (2% O2, 48 hours) or shorter duration severe chronic hypoxia (1% O2, 24 hours) did not affect
cell proliferation and NHE1 activity. In contrast, long term dimethyloxalylglycine (DMOG, Hif stabilizer) or zoniporide (NHE1 inhibitor) incubations
(21% O2, 24/48 hours) suppressed cell proliferation.
Conclusion: When our published and current results in this study interpreted together, at a critical level and duration of chronic hypoxia, Hif
mediated downregulation of NHE1 activity could suppress tumor cell proliferation regardless of the well-known anti-proliferative early term direct
effects of Hif. Therefore, restriction of NHE1 activity in tumor hypoxia is an important alternative target in regulating anti-proliferative action
against tumor cells.
Keywords
Cell culture techniques, hypoxia, sodium-hydrogen exchangers, neoplasms
Ethical Statement
The authors declared that this
research does not require ethical approval.
Informed Consent: Since the study was not conducted on
humans, consent was not obtained.
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