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Research ArticleArticle

Up-regulated Ectonucleotidases in Fas-Associated Death Domain Protein– and Receptor-Interacting Protein Kinase 1–Deficient Jurkat Leukemia Cells Counteract Extracellular ATP/AMP Accumulation via Pannexin-1 Channels during Chemotherapeutic Drug-Induced Apoptosis

Andrea M. Boyd-Tressler, Graham S. Lane and George R. Dubyak
Molecular Pharmacology July 2017, 92 (1) 30-47; DOI: https://doi.org/10.1124/mol.116.104000
Andrea M. Boyd-Tressler
Department of Physiology & Biophysics (G.S.L., G.R.D.), Department of Pharmacology (A.M.B.-T., G.R.D.), and Case Comprehensive Cancer Center (G.R.D.), School of Medicine, Case Western Reserve University, Cleveland, Ohio
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Graham S. Lane
Department of Physiology & Biophysics (G.S.L., G.R.D.), Department of Pharmacology (A.M.B.-T., G.R.D.), and Case Comprehensive Cancer Center (G.R.D.), School of Medicine, Case Western Reserve University, Cleveland, Ohio
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George R. Dubyak
Department of Physiology & Biophysics (G.S.L., G.R.D.), Department of Pharmacology (A.M.B.-T., G.R.D.), and Case Comprehensive Cancer Center (G.R.D.), School of Medicine, Case Western Reserve University, Cleveland, Ohio
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Abstract

Pannexin-1 (Panx1) channels mediate the efflux of ATP and AMP from cancer cells in response to induction of extrinsic apoptosis by death receptors or intrinsic apoptosis by chemotherapeutic agents. We previously described the accumulation of extracellular ATP /AMP during chemotherapy-induced apoptosis in Jurkat human leukemia cells. In this study, we compared how different signaling pathways determine extracellular nucleotide pools in control Jurkat cells versus Jurkat lines that lack the Fas-associated death domain (FADD) or receptor-interacting protein kinase 1 (RIP1) cell death regulatory proteins. Tumor necrosis factor-α induced extrinsic apoptosis in control Jurkat cells and necroptosis in FADD-deficient cells; treatment of both lines with chemotherapeutic drugs elicited similar intrinsic apoptosis. Robust extracellular ATP/AMP accumulation was observed in the FADD-deficient cells during necroptosis, but not during apoptotic activation of Panx1 channels. Accumulation of extracellular ATP/AMP was similarly absent in RIP1-deficient Jurkat cells during apoptotic responses to chemotherapeutic agents. Apoptotic activation triggered equivalent proteolytic gating of Panx1 channels in all three Jurkat cell lines. The differences in extracellular ATP/AMP accumulation correlated with cell-line–specific expression of ectonucleotidases that metabolized the released ATP/AMP. CD73 mRNA, and α.β-methylene-ADP-inhibitable ecto-AMPase activity were elevated in the FADD-deficient cells. In contrast, the RIP1-deficient cells were defined by increased expression of tartrate-sensitive prostatic acid phosphatase as a broadly acting ectonucleotidase. Thus, extracellular nucleotide accumulation during regulated tumor cell death involves interplay between ATP/AMP efflux pathways and different cell-autonomous ectonucleotidases. Differential expression of particular ectonucleotidases in tumor cell variants will determine whether chemotherapy-induced activation of Panx1 channels drives accumulation of immunostimulatory ATP versus immunosuppressive adenosine within the tumor microenvironment.

Footnotes

    • Received February 23, 2016.
    • Accepted April 26, 2017.
  • This work was supported by grants from the National Institutes of Health Institute of General Medical Sciences [grants R01-GM36387 and T32-GM00803] and National Eye Institute [R01-EY014362].

  • https://doi.org/10.1124/mol.116.104000.

  • Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 92 (1)
Molecular Pharmacology
Vol. 92, Issue 1
1 Jul 2017
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Up-regulated Ectonucleotidases in Fas-Associated Death Domain Protein– and Receptor-Interacting Protein Kinase 1–Deficient Jurkat Leukemia Cells Counteract Extracellular ATP/AMP Accumulation via Pannexin-1 Channels during Chemotherapeutic Drug-Induced Ap…
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Research ArticleArticle

Ectonucleotidases Modulate Apoptotic ATP/AMP Accumulation

Andrea M. Boyd-Tressler, Graham S. Lane and George R. Dubyak
Molecular Pharmacology July 1, 2017, 92 (1) 30-47; DOI: https://doi.org/10.1124/mol.116.104000

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Research ArticleArticle

Ectonucleotidases Modulate Apoptotic ATP/AMP Accumulation

Andrea M. Boyd-Tressler, Graham S. Lane and George R. Dubyak
Molecular Pharmacology July 1, 2017, 92 (1) 30-47; DOI: https://doi.org/10.1124/mol.116.104000
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