화학공학소재연구정보센터
Biochemical and Biophysical Research Communications, Vol.519, No.1, 153-159, 2019
Ammonia mediates mitochondrial uncoupling and promotes glycolysis via HIF-1 activation in human breast cancer MDA-MB-231 cells
It has been reported that ammonia produced by glutaminolysis activates the HIF-1 pathway in several types of cancer cells, but the underlying mechanisms remain unclear. In this study, the effects of ammonia on the activation of HIF-1 pathway and glycolysis in MDA-MB-231 breast cancer cells were investigated and the underlying mechanisms involved were elucidated. The results showed that NH4Cl concentration-dependently increased the protein level of HIF-1 alpha and enhanced the transactivation activity of HIF-1 in MDA-MB-231 cells. In addition, NH4Cl increased the expression of GIuT1 and LDHA and promoted aerobic glycolysis by activating the HIF-1 pathway. Further study revealed that NH4Cl increased the mitochondrial ROS level and decreased the cellular Fe2+ level in MDA-MB-231 cells. Activation of the HIF-1 pathway induced by NH4Cl was inhibited by addition of the antioxidant NAC or the NADPH oxidase (NOX) inhibitor apocynin, indicating the involvement of the NOX-induced ROS generation. When MDA-MB-231 cells were treated with NH4Cl, the oxygen consumption of cells increased, followed by the decreased mitochondrial membrane potential and cellular ATP level, indicating the uncoupling of mitochondria. In conclusion, NH4Cl activated the HIF-1 signaling pathway and promoted aerobic glycolysis in MDA-MB-231 cells, likely through the promotion of mitochondrial ROS release and mitochondrial uncoupling. (C) 2019 Elsevier Inc. All rights reserved.