Cutting off the power: inhibition of leukemia cell growth by pausing basal ATP release and P2X receptor signaling?

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• 作者：Carola Ledderose ; Tobias Woehrle ; Stephan Ledderose…
• 关键词：Purinergic signaling ; Mitochondria ; P2X receptors ; T lymphocytes ; Jurkat T cells ; Proliferation
• 刊名：Purinergic Signalling
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：12
• 期：3
• 页码：439-451
• 全文大小：2,577 KB
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Biomedicine
  Pharmacology and Toxicology
  Human Physiology
  Neurosciences
  Cancer Research
  
• 出版者：Springer Netherlands
• ISSN：1573-9546
• 卷排序：12

文摘

T cells respond to antigen stimulation with the rapid release of cellular ATP, which stimulates an autocrine feedback mechanism that regulates calcium influx through P2X receptors. This autocrine purinergic feedback mechanism plays an essential role in the activation of T cells resulting in cell proliferation and clonal expansion. We recently reported that increases in mitochondrial ATP production drive this stimulation-induced purinergic signaling mechanism but that low-level mitochondrial ATP production fuels basal T cell functions required to maintain vigilance of unstimulated T cells. Here we studied whether defects in these purinergic signaling mechanisms are involved in the unwanted proliferation of leukemia T cells. We found that acute leukemia T cells (Jurkat) possess a larger number and more active mitochondria than their healthy counterparts. Jurkat cells have higher intracellular ATP concentrations and generat more extracellular ATP than unstimulated T cells from healthy donors. As a result, increased purinergic signaling through P2X1 and P2X7 receptors elevates baseline levels of cytosolic Ca2+ in Jurkat cells. We found that pharmacological inhibition of this basal purinergic signaling mechanism decreases mitochondrial activity, Ca2+ signaling, and cell proliferation. Similar results were seen in the leukemic cell lines THP-1, U-937, and HL-60. Combined treatment with inhibitors of P2X1 or P2X7 receptors and the chemotherapeutic agent 6-mercaptopurine completely blocked Jurkat cell proliferation. Our results demonstrate that increased mitochondrial metabolism promotes autocrine purinergic signaling and uncontrolled proliferation of leukemia cells. These findings suggest that deranged purinergic signaling can result in T cell malignancy and that therapeutic targeting aimed at purinergic signaling is a potential strategy to combat T cell leukemia.