Extracellular ATP, as an energy and phosphorylating molecule, induces different types of drug resistances in cancer cells through ATP internalization and intracellular ATP level increase

// Xuan Wang 1, 2, 3 , Yunsheng Li 3 , Yanrong Qian 3 , Yanyang Cao 1, 2, 3 , Pratik Shriwas 1, 2, 3 , Haiyun Zhang 1, 2, 3 and Xiaozhuo Chen 1, 2, 3, 4, 5 1 Department of Biological Sciences, Ohio University, Athens, Ohio 45701, USA 2 Interdisciplinary Graduate Program in Molecular and Cellular Biology, Ohio University, Athens, Ohio 45701, USA 3 The Edison Biotechnology Institute, Ohio University, Athens, Ohio 45701, USA 4 Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio 45701, USA 5 Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701, USA Correspondence to: Xiaozhuo Chen, email: chenx@ohio.edu Keywords: the Warburg effect, tumor microenvironment, cancer metabolism, PDGFR, sunitinib Received: June 12, 2017      Accepted: August 16, 2017      Published: September 23, 2017 ABSTRACT Cancer cells are able to uptake extracellular ATP (eATP) via macropinocytosis to elevate intracellular ATP (iATP) levels, enhancing their survival in drug treatment. However, the involved drug resistance mechanisms are unknown. Here we investigated the roles of eATP as either an energy or a phosphorylating molecule in general drug resistance mediated by ATP internalization and iATP elevation. We report that eATP increased iATP levels and promoted drug resistance to various tyrosine kinase inhibitors (TKIs) and chemo-drugs in human cancer cell lines of five cancer types. In A549 lung cancer cells, the resistance was downregulated by macropinocytosis inhibition or siRNA knockdown of PAK1, an essential macropinocytosis enzyme. The elevated iATP upregulated the efflux activity of ABC transporters in A549 and SK-Hep-1 cells as well as phosphorylation of PDGFRα and proteins in the PDGFR-mediated Akt-mTOR and Raf-MEK signaling pathways in A549 cells. Similar phosphorylation upregulations were found in A549 tumors. These results demonstrate that eATP induces different types of drug resistance by eATP internalization and iATP elevation, implicating the ATP-rich tumor microenvironment in cancer drug resistance, expanding our understanding of the roles of eATP in the Warburg effect and offering new anticancer drug resistance targets.