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Internalization of Extracellular ATP by Cancer Cells and its Functional Roles in Cancer Drug Resistance

Wang, Xuan
http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1505834714683835

Abstract Details

2017, Doctor of Philosophy (PhD), Ohio University, Biological Sciences (Arts and Sciences).
Cancer is the second leading cause of death in the US. Despite the endeavors and achievements made in treating cancers during the past decades, resistance to classical chemotherapeutic agents and/or novel targeted drugs has been remaining to be a major problem in cancer therapies. Drug resistance, either existing before treatment (intrinsic) or generated after therapy (acquired), is responsible for most relapses of cancer, one of the major causes of death of the disease. Heterogeneity among patients and tumors, and the versatility of cancer to circumvent therapies make drug resistance more challenging to deal with. Better understanding the mechanisms of drug resistance is required to provide guidance to future cancer treatment and achieve better outcomes. Dysfunctional energetics and opportunistic uptake of extracellular molecules have been named as emerging hallmarks of cancer and cancer metabolism, respectively. 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-providing 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 as well as phosphorylation of PDGFRa and proteins in the PDGFR-mediated Akt-mTOR and Raf-MEK signaling pathways. Similar phosphorylation upregulations were found in A549 tumors. Meanwhile, the resistance cannot be attributed to the overall purinergic receptor-mediated signaling or intracellular ATP synthesis. 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.
Xiaozhuo Chen (Advisor)
Shiyong Wu (Committee Member)
Robert Colvin (Committee Member)
Fabian Benencia (Committee Member)
124 p.
Biology; Cellular Biology; Molecular Biology
Cancer; drug resistance; ATP; macropinocytosis; ABC transporter; tumor microenvironment, Warburg effect

Recommended Citations

Citations

  • Wang, X. (2017). Internalization of Extracellular ATP by Cancer Cells and its Functional Roles in Cancer Drug Resistance [Doctoral dissertation, Ohio University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1505834714683835

    APA Style (7th edition)

  • Wang, Xuan. Internalization of Extracellular ATP by Cancer Cells and its Functional Roles in Cancer Drug Resistance. 2017. Ohio University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1505834714683835.

    MLA Style (8th edition)

  • Wang, Xuan. "Internalization of Extracellular ATP by Cancer Cells and its Functional Roles in Cancer Drug Resistance." Doctoral dissertation, Ohio University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1505834714683835

    Chicago Manual of Style (17th edition)

ohiou1505834714683835
154
© 2017, all rights reserved.
This open access ETD is published by Ohio University and OhioLINK.