Extracellular ATP is internalized by macropinocytosis and induces intracellular ATP increase and drug resistance in cancer cells

Yanrong Qian; Xuan Wang; Yi Liu; Yunsheng Li; Robert A Colvin; Lingying Tong; Shiyong Wu; Xiaozhuo Chen

doi:10.1016/j.canlet.2014.06.008

Extracellular ATP is internalized by macropinocytosis and induces intracellular ATP increase and drug resistance in cancer cells

Cancer Lett. 2014 Sep 1;351(2):242-51. doi: 10.1016/j.canlet.2014.06.008. Epub 2014 Jun 26.

Authors

Yanrong Qian¹, Xuan Wang², Yi Liu², Yunsheng Li³, Robert A Colvin⁴, Lingying Tong¹, Shiyong Wu¹, Xiaozhuo Chen⁵

Affiliations

¹ Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA; Interdisciplinary Graduate Program in Molecular and Cellular Biology, Ohio University, Athens, OH 45701, USA; The Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA.
² Department of Biological Sciences, Ohio University, Athens, OH 45701, USA; Interdisciplinary Graduate Program in Molecular and Cellular Biology, Ohio University, Athens, OH 45701, USA; The Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA.
³ The Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA.
⁴ Department of Biological Sciences, Ohio University, Athens, OH 45701, USA; Interdisciplinary Graduate Program in Molecular and Cellular Biology, Ohio University, Athens, OH 45701, USA.
⁵ Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA; Department of Biological Sciences, Ohio University, Athens, OH 45701, USA; Department of Biomedical Sciences, Ohio University, Athens, OH 45701, USA; Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA; Interdisciplinary Graduate Program in Molecular and Cellular Biology, Ohio University, Athens, OH 45701, USA; The Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA. Electronic address: chenx@ohio.edu.

PMID: 24973521
DOI: 10.1016/j.canlet.2014.06.008

Abstract

ATP plays central roles in cancer metabolism and the Warburg effect. Intratumoral ATP concentrations are up to 10(4) times higher than those of interstitial ATP in normal tissues. However, extracellular ATP is not known to enter cancer cells. Here we report that human A549 lung cancer cells internalized extracellular ATP by macropinocytosis as demonstrated by colocalization of a nonhydrolyzable fluorescent ATP and a macropinocytosis tracer high-molecular-weight dextran, as well as by a macropinocytosis inhibitor study. Extracellular ATP also induced increase of intracellular ATP levels, without involving transcription and translation at significant levels, and cancer cells' resistance to ATP-competitor anticancer drugs, likely through the mechanism of ATP internalization. These findings, described for the first time, have profound implications in ATP-sharing among cancer cells in tumors and highlight a novel anticancer target.

Keywords: Cancer metabolism; Kras; Nonhydrolyzable fluorescent ATP; Receptor tyrosine kinase; Warburg effect.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism*
Adenosine Triphosphate / pharmacokinetics
Adenosine Triphosphate / pharmacology
Adenylate Kinase / metabolism
Antineoplastic Agents / pharmacology*
Cell Growth Processes / physiology
Cell Line, Tumor
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Extracellular Space / metabolism
Glycolysis
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / metabolism*
Oxidative Phosphorylation
Phosphorylation
Pinocytosis
Protein Kinase Inhibitors / pharmacology
Protein-Tyrosine Kinases / metabolism

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Adenosine Triphosphate
Protein-Tyrosine Kinases
Adenylate Kinase