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

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. 15 samples consisting of 3 sorted fractions from PEO1 human ovarian cancer cells grown with RPMI-1640 + 10% FBS in triplicate.