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

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

Oncotarget (2018-02-01)
Shojiro Kitajima, Kian Leong Lee, Hiroki Hikasa, Wendi Sun, Ruby Yun-Ju Huang, Henry Yang, Shinji Matsunaga, Takehiro Yamaguchi, Marito Araki, Hiroyuki Kato, Lorenz Poellinger
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.

MATERIALS
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Product Description

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