Abstract 1703: Extracellular ATP mediated intracellular ATP increase: Evidence for transport of extracellular ATP into cancer cells.
Authors: Qian Yanrong , Liu Yi , Wang Xuan , Chen Xiaozhuo 
Published: August 2014

ATP as a most common cofactor of enzymatic reactions and a universal source of bioenergy transfer plays central metabolic and signal transduction roles in normal and cancer cells. Almost all cancer cells switch from the highly efficient mitochondrial oxidative phosphorylation to low efficiency glycolysis for ATP synthesis, a phenomenon called the Warburg effect that remains to be fully understood. Despite the low efficiency glycolysis, cancer cells appear to have no shortage of ATP under any circumstance examined. Different from cell culture media, high concentrations of extracellular ATP is present in the blood and in cancer. Although ample evidence indicates intratumoral (extracellular) ATP concentration is higher than other parts of the body, it is presently unclear about the sources and fates of intratumoral/extracellular ATP and how they affect intracellular ATP. ATP is not known to cross plasma membrane and there is no known plasma membrane associated ATP transporter. We previously reported drastic increases of intracellular ATP concentration and rescue of glucose deprived A549 human lung cancer cells by addition of extracellular ATP.1 We hypothesized that the increased intracellular ATP is a result of extracellular ATP taken up by cancer cells. To test this hypothesis, we studied extracellular ATP-induced intracellular ATP increase in A549 lung and other cancer and non-tumorigenic cells using the ATP assay. Here we report (i) Extracellular ATP increased intracellular ATP of A549 cells in a dose- and time-dependent manners. (ii) The ATP increase was also observed even when cells’ mitochondrial ATP synthesis and/or glycolysis were blocked. (iii) Extracellular ATP at 3 mM also induced a sharp and temporary ATP surge (peak) several hours after the inhibition described in (ii) and the surge was absent in the nontumorigenic cell lines under the same conditions. (iv) The timing of the surge appeared to be dependent upon extracellular ATP concentration. (v) Extracellular ATP led to changes in energy status sensing protein AMPK and its phosphorylation. All these results indicate that extracellular ATP exerts profound effects on intracellular ATP and suggest a possible direct ATP transport mechanism into cancer cells. These results strongly suggest that cancer cells supplement their ATP need with extracellular ATP and extracellular ATP may play some vitally important but previously unrecognized roles in the Warburg effect and tumorigenesis. These new findings challenge the current view that extracellular ATP functions only through plasma membrane receptors and force us to rethink the roles of extracellular ATP played in cancer metabolism, energy homeostasis, as well as the symbiotic relationship between cancer cells and between cancer and normal / stromal cells. They also imply a new strategy for cancer treatment.

1.Liu, Y., et al., Mol. Cancer Ther. 2012, 11:1672-1682.

Citation Format: Yanrong Qian, Yi Liu, Xuan Wang, Xiaozhuo Chen. Extracellular ATP mediated intracellular ATP increase: Evidence for transport of extracellular ATP into cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1703. doi:10.1158/1538-7445.AM2013-1703