PT - JOURNAL ARTICLE AU - Andrea M Boyd-Tressler AU - Graham S Lane AU - George R Dubyak TI - Upregulated ectonucleotidases in FADD- and RIP1-deficient Jurkat leukemia cells counteract extracellular ATP/AMP accumulation via pannexin-1 channels during chemotherapeutic drug-induced apoptosis AID - 10.1124/mol.116.104000 DP - 2017 Jan 01 TA - Molecular Pharmacology PG - mol.116.104000 4099 - http://molpharm.aspetjournals.org/content/early/2017/05/01/mol.116.104000.short 4100 - http://molpharm.aspetjournals.org/content/early/2017/05/01/mol.116.104000.full AB - 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 FADD or RIP1 cell death regulatory proteins. TNF-α induced extrinsic apoptosis in control Jurkat cells but 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 ecto-nucleotidases. 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.