Hypoxia-inducible factor-1α regulates energy fuel metabolism and mediates metabolic plasticity during ammonia stress response in ovarian cancer stem-like cells

[Speaker] Shojiro Kitajima:1,5
[Co-author] Kian Leong Lee:2, Hiroki Hikasa:3, Shinji Matsunaga:1, Takehiro Yamaguchi:1, Shuhei Tomita:1, Marito Araki:4, Hiroyuki Kato:5, Lorenz Poellinger:5
1:Pharmacology, Osaka City University Graduate School of Medicine, Japan, 2:Cancer & Stem Cell Biology Program, Duke-NUS Medical School, Singapore, 3:Department of Biochemistry, School of Medicine, The University of Occupational and Environmental Health, Japan, 4:Department of Transfusion Medicine and Stem Cell Regulation, Juntendo University Graduate School of Medicine, Japan, 5:Cancer Science Institute of Singapore, National University of Singapore, Singapore

Ammonia is produced by cancer cells as a by-product of glutamine metabolism during rapid cell growth. Although the toxicity of ammonia has been well known, specific factors that deal with ammonia-induced cellular stress and regulate cell metabolism to survive have yet to be identified. We demonstrated that the hypoxia-inducible factor-1α (HIF-1α) is stabilised and activated during ammonia stress response. The ablation of HIF-1α promoted apoptosis caused by high levels of ammonia. Moreover, 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 marked by the expression of CD90. Interestingly, activated HIF-1α counteracts GS function in glutamine metabolism by facilitating glycolysis leading to elevated glucose dependency. Our studies reveal the hitherto unknown functions of HIF-1α that promote metabolic plasticity during ammonia stress response in the cancer stem-like cells where GS facilitates cell proliferation and HIF-1α contributes to remodeling in energy fuel usage resulting in attenuated proliferation but conversely promoting cell survival.

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