Research Papers:

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

Shojiro Kitajima _, Kian Leong Lee, Hiroki Hikasa, Wendi Sun, Ruby Yun-Ju Huang, Henry Yang, Shinji Matsunaga, Takehiro Yamaguchi, Marito Araki, Hiroyuki Kato and Lorenz Poellinger

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Oncotarget. 2017; 8:114481-114494. https://doi.org/10.18632/oncotarget.23010

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Shojiro Kitajima1,2, Kian Leong Lee1,3, Hiroki Hikasa4, Wendi Sun1,5, Ruby Yun-Ju Huang1, Henry Yang1, Shinji Matsunaga2, Takehiro Yamaguchi2, Marito Araki6, Hiroyuki Kato1 and Lorenz Poellinger1,7,*

1Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

2Pharmacology, Graduate School of Medicine, Osaka City University, Osaka, Japan

3Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore

4Department of Biochemistry, School of Medicine, The University of Occupational and Environmental Health, Kitakyushu, Japan

5School of Biological Sciences, Nanyang Technological University, Singapore, Singapore

6Department of Transfusion Medicine and Stem Cell Regulation, Juntendo University Graduate School of Medicine, Tokyo, Japan

7Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden


Correspondence to:

Shojiro Kitajima, email: [email protected]

Keywords: hypoxia-inducible factors; ammonia; glutamine synthetase; energy metabolism; cancer stem cells

Received: August 24, 2017     Accepted: November 10, 2017     Published: December 07, 2017


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.

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