Mechanisms of Extracellular Nucleotide Accumulation During Regulated Cell Death in Tumor Cells

Download or read book Mechanisms of Extracellular Nucleotide Accumulation During Regulated Cell Death in Tumor Cells written by Andrea Michelle Boyd Tressler and published by . This book was released on 2016 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Accumulation of extracellular adenine nucleotides is a key regulator of the purinergic anti-tumor immune response that is triggered after treatment with certain chemotherapeutic agents. ATP released from dying tumor cells has been shown to engage P2 purinergic receptors on nearby leukocytes to activate this response. Conversely, accumulation of adenosine within the tumor microenvironment causes suppression of the immune response. The balance between ATP and adenosine in the tumor microenvironment can dictate the aggressiveness of the cancer and its response to chemotherapy treatment. To examine the regulated release of ATP and its metabolites, as well as their extracellular accumulation, we conducted three main studies. In the first study, we used human leukemic Jurkat T cells to characterize the role of Pannexin 1 (Panx1) channels in the release of ATP during treatment with three chemotherapeutic agents: doxorubicin (Dox), Etoposide (Etop), and staurosporine (STS). These diverse pro-apoptotic drugs were able to induce functional activation of the Panx1 channel by cleavage of the autoinhibitory C terminal domain. Activation of Panx1 led to the release of ATP, but the majority of nucleotide release was in the form of ADP and AMP. Our second study examined the how different rates of adenine nucleotide release and ectometabolism dictate the composition of pro- or anti- inflammatory nucleotides using Jurkat T cells that included clonal variants lacking either FADD or RIP1and treated with pro-apoptotic chemotherapeutic drugs. Despite similar apoptotic induction, the accumulation of ATP+ADP+AMP was decreased in the clonal variants and this decrease was linked to increased expression of the ectonucleotidase CD73. Finally, we explored the role of Panx1-mediated ATP release in the murine lymphoma cell line, EG7, that have been used for in vivo studies of the purinergic anti-tumor immune response. We discover that while the EG7 cells activate Panx1 and release adenine nucleotides, the release is independent of Panx1. Together these studies provide further understanding of the regulated release and accumulation of ATP, ADP, and AMP within the tumor microenvironment after treatment with chemotherapeutic drugs.