Extracellular ATP is internalized by macropinocytosis and induces intracellular ATP increase and drug resistance in cancer cells
Extracellular ATP is internalized by macropinocytosis and induces intracellular ATP increase and drug resistance in cancer cells
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DOI：
10.1016/j.canlet.2014.06.008
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发表时间：
2014-09-01
期刊：
影响因子：
9.7
通讯作者：
Chen, Xiaozhuo
中科院分区：
文献类型：
--
作者：
Qian, Yanrong;Wang, Xuan;Chen, Xiaozhuo
ATP在癌症代谢和瓦尔堡效应中起着核心作用。肿瘤内ATP浓度比正常组织间质ATP浓度高10（4）倍。然而，细胞外ATP不知道进入癌细胞。在这里，我们报告说，人类A549肺癌细胞内化细胞外ATP的巨胞饮作用所证明的非水解荧光ATP和巨胞饮示踪剂高分子量葡聚糖的共定位，以及由巨胞饮抑制剂的研究。细胞外ATP还诱导细胞内ATP水平的增加，而不涉及显著水平的转录和翻译，以及癌细胞对ATP竞争剂抗癌药物的抗性，可能通过ATP内化机制。这些首次描述的发现对肿瘤中癌细胞之间的ATP共享具有深远的影响，并突出了一种新的抗癌靶点。(C)2014爱思唯尔爱尔兰有限公司版权所有。
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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.