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Internalization of Extracellular ATP in Cancer Cells and Development of New Generations of Anticancer Glucose Transport Inhibitors
Qian, Yanrong

2014, Doctor of Philosophy (PhD), Ohio University, Molecular and Cellular Biology (Arts and Sciences).
The past decade has witnessed remarkable progress toward understanding the reprogrammed metabolism in cancer, an emerging hallmark as well as an active area of basic, translational, and clinical research. About ninety years ago, Otto Warburg pioneered quantitative investigations of cancer metabolism and discovered that cancer cells exhibit a phenotype of increased glycolysis even under aerobic conditions, known as the Warburg effect. Warburg speculated that the reason for the upregulated glycolysis was for compensating the ATP shortage due to dysfunctions of mitochondria in cancer cells. Despite subsequent progresses, the biological reasons for ATP synthesis by aerobic glycolysis in cancer cells are only partially understood. Intriguingly, intratumoral (extracellular) ATP levels are 103 to 104 times higher than those in normal tissues. We showed that although extracellular ATP is not known to cross the plasma membrane by itself, extracellular ATP in the range of the intratumoral ATP levels induced large intracellular ATP concentration increase in A549 human lung cancer cells and promoted cancer cell survival. More importantly, we reported that a nonhydrolyzable fluorescent ATP was internalized by A549 cells through macropinocytosis as visualized by fluorescence microscopy. The induced ATP increase was reduced by the macropinocytosis inhibitor EIPA but persisted even when mitochondrial oxidative phosphorylation and glycolysis were inhibited, without involving transcription or translation. The increases were also observed in several other cancer cell lines, but not in noncancerous cells. Furthermore, extracellular ATP enhanced cancer cell survival under various stress conditions and promoted drug resistance to tyrosine kinase inhibitors that compete with ATP for their anticancer action. Collectively, these results provide the first piece of evidence that extracellular ATP is internalized by cancer cells via macropinocytosis and potentially other endocytic process, which significantly contribute to their growth and to drug resistance. These findings potentially change our understanding of ATP supply and sharing among cancer cells, enhance our understanding of the Warburg effect, and highlight a novel anticancer target. Current understanding of glucose transport and metabolism in cancer, anticancer therapeutics targeting glycolysis and glucose transporters, and daunting challenges are also summarized. Based on the previous discovery on WZB-117, the first generation of glucose transport inhibitor, we screened a library of its derivatives and identified WZB-173 and DRB-18 with higher stabilities and potencies as lead compounds in new generations of novel glucose transport inhibitors. Both compounds can serve as models for further development of glucose transport inhibitors.
Xiaozhuo Chen (Advisor)
Shiyong Wu (Committee Member)
Stephen Bergmeier (Committee Member)
Fabian Benencia (Committee Member)
220 p.

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Qian, Y. (2014). Internalization of Extracellular ATP in Cancer Cells and Development of New Generations of Anticancer Glucose Transport Inhibitors. (Electronic Thesis or Dissertation). Retrieved from https://etd.ohiolink.edu/

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Qian, Yanrong. "Internalization of Extracellular ATP in Cancer Cells and Development of New Generations of Anticancer Glucose Transport Inhibitors." Electronic Thesis or Dissertation. Ohio University, 2014. OhioLINK Electronic Theses and Dissertations Center. 10 Dec 2017.

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Qian, Yanrong "Internalization of Extracellular ATP in Cancer Cells and Development of New Generations of Anticancer Glucose Transport Inhibitors." Electronic Thesis or Dissertation. Ohio University, 2014. https://etd.ohiolink.edu/

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