title: Extracellular ATP is internalized by macropinocytosis and induces intracellular ATP increase and drug resistance in cancer cells.
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.
authors: 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.
authors: Yanrong
authors: Y
authors: Qian
authors: 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.
authors: Xuan
authors: X
authors: Wang
authors: 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.
authors: Yi
authors: Y
authors: Liu
authors: The Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA.
authors: Yunsheng
authors: Y
authors: Li
authors: Department of Biological Sciences, Ohio University, Athens, OH 45701, USA; Interdisciplinary Graduate Program in Molecular and Cellular Biology, Ohio University, Athens, OH 45701, USA.
authors: Robert A
authors: RA
authors: Colvin
authors: 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.
authors: Lingying
authors: L
authors: Tong
authors: 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.
authors: Shiyong
authors: S
authors: Wu
authors: 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.
authors: Xiaozhuo
authors: X
authors: Chen
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D000263:Adenylate Kinase / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005110:Extracellular Space / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010766:Phosphorylation; D010873:Pinocytosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; D000263:Adenylate Kinase
keywords: Cancer metabolism; Kras; Nonhydrolyzable fluorescent ATP; Receptor tyrosine kinase; Warburg effect