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

// Shojiro Kitajima 1, 2 , Kian Leong Lee 1, 3 , Hiroki Hikasa 4 , Wendi Sun 1, 5 , Ruby Yun-Ju Huang 1 , Henry Yang 1 , Shinji Matsunaga 2 , Takehiro Yamaguchi 2 , Marito Araki 6 , Hiroyuki Kato 1 and Lorenz Poellinger 1, 7, * 1 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore 2 Pharmacology, Graduate School of Medicine, Osaka City University, Osaka, Japan 3 Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore 4 Department of Biochemistry, School of Medicine, The University of Occupational and Environmental Health, Kitakyushu, Japan 5 School of Biological Sciences, Nanyang Technological University, Singapore, Singapore 6 Department of Transfusion Medicine and Stem Cell Regulation, Juntendo University Graduate School of Medicine, Tokyo, Japan 7 Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden * Decease Correspondence to: Shojiro Kitajima, email: kitajima.shojiro@med.osaka-cu.ac.jp Keywords: hypoxia-inducible factors; ammonia; glutamine synthetase; energy metabolism; cancer stem cells Received: August 24, 2017      Accepted: November 10, 2017      Published: December 07, 2017 ABSTRACT 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-1α (HIF-1α) is stabilized 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 under ammonia stress and glutamine-dependent metabolism 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 a biphasic ammonia stress management in the cancer stem-like cells where GS facilitates cell proliferation and HIF-1α contributes to the metabolic remodeling in energy fuel usage resulting in attenuated proliferation but conversely promoting cell survival.