Journal
ONCOTARGET
Volume 8, Issue 70, Pages 114481-114494Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.23010
Keywords
hypoxia-inducible factors; ammonia; glutamine synthetase; energy metabolism; cancer stem cells
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Funding
- Singapore National Research Foundation [R-713-005-014-271]
- Singapore Ministry of Health's National Medical Research Council [NMRC/CIRG/1389/2014]
- Terry Fox Foundation [R-713-000-193-597]
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Ammonia is a toxic by-product of metabolism that causes cellular stresses. Although a number of proteins are involved in adaptive stress response, specific factors that counteract ammonia-induced cellular stress and regulate cell metabolism to survive against its toxicity have yet to be identified. We demonstrated that the hypoxia-inducible factor-1 alpha (HIF-1 alpha) is stabilized and activated by ammonia stress. HIF-1 alpha activated by ammonium chloride compromises ammonia-induced apoptosis. Furthermore, we identified glutamine synthetase (GS) as a key driver of cancer cell proliferation under ammonia stress and glutamine-dependent metabolism in ovarian cancer stem-like cells expressing CD90. Interestingly, activated HIF-1 alpha counteracts glutamine synthetase function in glutamine metabolism by facilitating glycolysis and elevating glucose dependency. Our studies reveal the hitherto unknown functions of HIF-1 alpha in a biphasic ammonia stress management in the cancer stem-like cells where GS facilitates cell proliferation and HIF-1 alpha contributes to the metabolic remodeling in energy fuel usage resulting in attenuated proliferation but conversely promoting
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