WenJuan Wang and Xiao-xing Shi contributed equally to this work.
The mechanism underlying the effects of the cell surface ATP synthase on the regulation of intracellular acidification during acidosis†
Article first published online: 9 MAY 2013
Copyright © 2013 Wiley Periodicals, Inc.
Journal of Cellular Biochemistry
Volume 114, Issue 7, pages 1695–1703, July 2013
How to Cite
Wang, W.-j., Shi, X.-x., Liu, Y.-w., He, Y.-q., Wang, Y.-z., Yang, C.-x. and Gao, F. (2013), The mechanism underlying the effects of the cell surface ATP synthase on the regulation of intracellular acidification during acidosis. J. Cell. Biochem., 114: 1695–1703. doi: 10.1002/jcb.24511
- Issue published online: 9 MAY 2013
- Article first published online: 9 MAY 2013
- Accepted manuscript online: 5 FEB 2013 08:18AM EST
- Manuscript Accepted: 24 JAN 2013
- Manuscript Received: 5 JUN 2012
- The National High Technology Research and Development Program of China (863 Program). Grant Number: 2008AA 02Z121
- National Natural Science Foundation of China. Grant Numbers: 81071814, 81172027
- Program of Shanghai Subject Chief Scientist. Grant Number: 11XD1404000
- Science and Technology Commission of the Shanghai Municipality (Key Technology Support Program). Grant Number: 10411950500
- CELL SURFACE ATP SYNTHASE;
- INTRACELLULAR ACIDIFICATION;
The F1F0 ATP synthase has recently become the focus of anti-cancer research. It was once thought that ATP synthases were located strictly on the inner mitochondrial membrane; however, in 1994, it was found that some ATP synthases localized to the cell surface. The cell surface ATP synthases are involved in angiogenesis, lipoprotein metabolism, innate immunity, hypertension, the regulation of food intake, and other processes. Inhibitors of this synthase have been reported to be cytotoxic and to induce intracellular acidification. However, the mechanisms by which these effects are mediated and the molecular pathways that are involved remain unclear. In this study, we aimed to determine whether the inhibition of cell proliferation and the induction of cell apoptosis that are induced by inhibitors of the cell surface ATP synthase are associated with intracellular acidification and to investigate the mechanism that underlines the effects of this inhibition, particularly in an acidic tumor environment. We demonstrated that intracellular acidification contributes to the cell proliferation inhibition that is mediated by cell surface ATP synthase inhibitors, but not to the induction of apoptosis. Intracellular acidification is only one of the mechanisms of ecto-ATP synthase-targeted antitumor drugs. We propose that intracellular acidification in combination with the inhibition of cell surface ATP generation induce cell apoptosis after cell surface ATP synthase blocked by its inhibitors. A better understanding of the mechanisms activated by ecto-ATP synthase-targeted cancer therapies may facilitate the development of potent anti-tumor therapies, which target this enzyme and do not exhibit clinical limitations. J. Cell. Biochem. 114: 1695–1703, 2013. © 2013 Wiley Periodicals, Inc.