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

ABSTRACT: 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-1α (HIF-1α) is stabilised and activated by ammonia stress. HIF-1α 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-1α counteracts glutamine synthetase function in glutamine metabolism by facilitating glycolysis and elevating glucose dependency. Our studies reveal the hitherto unknown functions of HIF-1α in biphasic ammonia stress management in cancer stem-like cells. GS facilitates proliferation and HIF-1α contributes to metabolic remodelling in cellular energy usage resulting in attenuated proliferation but conversely promoting cell survival.

ORGANISM(S): Homo sapiens

PROVIDER: GSE107251 | GEO | 2017/11/22

SECONDARY ACCESSION(S): PRJNA419419

REPOSITORIES: GEO

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CP001: Modulation of glutamine metabolism by the PI3K-PKB/c-akt-FOXO network regulates autophagy

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CP003: Modulation of glutamine metabolism by the PI3K-PKB/c-akt-FOXO network regulates autophagy

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