title: Cutting off the power: inhibition of leukemia cell growth by pausing basal ATP release and P2X receptor signaling?
abstract: 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 Ca(2+) in Jurkat cells. We found that pharmacological inhibition of this basal purinergic signaling mechanism decreases mitochondrial activity, Ca(2+) 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.
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA.
authors.forename: Carola
authors.initials: C
authors.lastname: Ledderose
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Woehrle
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ledderose
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA.
authors.forename: Katharina
authors.initials: K
authors.lastname: Strasser
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Seist
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA.
authors.forename: Jingping
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA. wjunger@bidmc.harvard.edu.|Ludwig Boltzmann Institute for Traumatology, 1200, Vienna, Austria. wjunger@bidmc.harvard.edu.
authors.forename: Wolfgang G
authors.initials: WG
authors.lastname: Junger
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000378:metabolism* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D058469:Receptors, Purinergic P2X / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D058469:Receptors, Purinergic P2X; D000255:Adenosine Triphosphate
keywords: Jurkat T cells; Mitochondria; P2X receptors; Proliferation; Purinergic signaling; T lymphocytes