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Accession IconGSE107251

Hypoxia-inducible factor-1 promotes cell survival during ammonia stress response in ovarian cancer stem-like cells

Organism Icon Homo sapiens
Sample Icon 15 Downloadable Samples
Technology Badge Icon Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)

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Description
Ammonia is a toxic by-product of metabolism that causes cellular stress. Although a number of proteins are involved in adaptive stress response, specific factors that counteract ammonia-induced cellular stress and regulate cell metabolism that facilitate survival against toxicity have yet to be identified. We demonstrated that hypoxia-inducible factor-1 (HIF-1) is stabilised and activated by ammonia stress. HIF-1 activated by ammonium chloride compromises ammonia-induced apoptosis. Furthermore, we identified glutamine synthetase (GS) as a key driver of cancer cell proliferation and glutamine-dependent metabolism under ammonia stress in ovarian cancer stem-like cells expressing CD90. Interestingly, activated HIF-1 counteracts glutamine synthetase function in glutamine metabolism by facilitating glycolysis and elevating glucose dependency. Our studies reveal the hitherto unknown functions of HIF-1 in biphasic ammonia stress management in cancer stem-like cells. GS facilitates proliferation and HIF-1 contributes to metabolic remodelling in cellular energy usage resulting in attenuated proliferation but conversely promoting cell survival.
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