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细胞外ATP作为一种能量和磷酸化分子，通过ATP内化和细胞内ATP水平升高，诱导癌细胞产生不同类型的耐药性。

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.

作者信息

Wang Xuan, Li Yunsheng, Qian Yanrong, Cao Yanyang, Shriwas Pratik, Zhang Haiyun, Chen Xiaozhuo

机构信息

Department of Biological Sciences, Ohio University, Athens, Ohio 45701, USA.

Interdisciplinary Graduate Program in Molecular and Cellular Biology, Ohio University, Athens, Ohio 45701, USA.

出版信息

Oncotarget. 2017 Sep 23;8(50):87860-87877. doi: 10.18632/oncotarget.21231. eCollection 2017 Oct 20.

DOI:10.18632/oncotarget.21231
PMID:29152126
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5675678/
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.

摘要

癌细胞能够通过巨胞饮作用摄取细胞外ATP（eATP），以提高细胞内ATP（iATP）水平，增强其在药物治疗中的存活率。然而，相关的耐药机制尚不清楚。在此，我们研究了eATP作为能量分子或磷酸化分子在由ATP内化和iATP升高介导的一般耐药性中的作用。我们报告称，eATP提高了iATP水平，并促进了五种癌症类型的人类癌细胞系对各种酪氨酸激酶抑制剂（TKIs）和化疗药物的耐药性。在A549肺癌细胞中，通过抑制巨胞饮作用或敲低PAK1（一种必需的巨胞饮作用酶）的小干扰RNA（siRNA），耐药性被下调。升高的iATP上调了A549和SK-Hep-1细胞中ABC转运蛋白的外排活性，以及A549细胞中PDGFRα的磷酸化和PDGFR介导的Akt-mTOR和Raf-MEK信号通路中的蛋白质磷酸化。在A549肿瘤中也发现了类似的磷酸化上调。这些结果表明，eATP通过eATP内化和iATP升高诱导不同类型的耐药性，提示富含ATP的肿瘤微环境与癌症耐药性有关，扩展了我们对eATP在瓦伯格效应中作用的理解，并提供了新的抗癌耐药靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9290/5675678/85ada56cc596/oncotarget-08-87860-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9290/5675678/795637d1ed98/oncotarget-08-87860-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9290/5675678/79f60d653e76/oncotarget-08-87860-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9290/5675678/6963472f9360/oncotarget-08-87860-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9290/5675678/092f2a7e99da/oncotarget-08-87860-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9290/5675678/d9f85ec88d90/oncotarget-08-87860-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9290/5675678/aef2041bc937/oncotarget-08-87860-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9290/5675678/85ada56cc596/oncotarget-08-87860-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9290/5675678/795637d1ed98/oncotarget-08-87860-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9290/5675678/79f60d653e76/oncotarget-08-87860-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9290/5675678/6963472f9360/oncotarget-08-87860-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9290/5675678/092f2a7e99da/oncotarget-08-87860-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9290/5675678/d9f85ec88d90/oncotarget-08-87860-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9290/5675678/aef2041bc937/oncotarget-08-87860-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9290/5675678/85ada56cc596/oncotarget-08-87860-g007.jpg

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