title: PARP-1 hyperactivation and reciprocal elevations in intracellular Ca2+ during ROS-induced nonapoptotic cell death.
abstract: The generation of reactive oxygen species (ROS) has been implicated in the pathogenesis of renal ischemia/reperfusion injury, and many other pathological conditions. DNA strand breaks caused by ROS lead to the activation of poly(ADP-ribose)polymerase-1 (PARP-1), the excessive activation of which can result in cell death. We have utilized a model in which 2,3,5-tris(glutathion-S-yl)hydroquinone (TGHQ), a nephrotoxic and nephrocarcinogenic metabolite of hydroquinone, causes ROS-dependent cell death in human renal proximal tubule epithelial cells (HK-2), to further elucidate the role of PARP-1 in ROS-dependent cell death. TGHQ-induced ROS generation, DNA strand breaks, hyperactivation of PARP-1, rapid depletion of nicotinamide adenine dinucleotide (NAD), elevations in intracellular Ca(2+) concentrations, and subsequent nonapoptotic cell death in both a PARP- and Ca(2+)-dependent manner. Thus, inhibition of PARP-1 with PJ34 completely blocked TGHQ-mediated accumulation of poly(ADP-ribose) polymers and NAD consumption, and delayed HK-2 cell death. In contrast, chelation of intracellular Ca(2+) with BAPTA completely abrogated TGHQ-induced cell death. Ca(2+) chelation also attenuated PARP-1 hyperactivation. Conversely, inhibition of PARP-1 modulated TGHQ-mediated changes in Ca(2+) homeostasis. Interestingly, PARP-1 hyperactivation was not accompanied by the translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus, a process usually associated with PARP-dependent cell death. Thus, pathways coupling PARP-1 hyperactivation to cell death are likely to be context-dependent, and therapeutic strategies designed to target PARP-1 need to recognize such variability. Our studies provide new insights into PARP-1-mediated nonapoptotic cell death, during which PARP-1 hyperactivation and elevations in intracellular Ca(2+) are reciprocally coupled to amplify ROS-induced nonapoptotic cell death.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Sciences Center, Tucson, Arizona 85721.
authors.forename: Fengjiao
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Sciences Center, Tucson, Arizona 85721 Department of Pediatrics and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla,CA 92093-0651.
authors.forename: Ruiye
authors.initials: R
authors.lastname: Xie
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Sciences Center, Tucson, Arizona 85721.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Munoz
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Sciences Center, Tucson, Arizona 85721.
authors.forename: Serrine S
authors.initials: SS
authors.lastname: Lau
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Sciences Center, Tucson, Arizona 85721 scouser@pharmacy.arizona.edu.
authors.forename: Terrence J
authors.initials: TJ
authors.lastname: Monks
mesh_terms: D002118:Calcium / Q000378:metabolism*; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000031:analogs & derivatives* / Q000633:toxicity; D006801:Humans; D006873:Hydroquinones / Q000633:toxicity*; D007687:Kidney Tubules, Proximal / Q000166:cytology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D006873:Hydroquinones; D017382:Reactive Oxygen Species; C078765:2,3,5-(triglutathion-S-yl)hydroquinone; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D005978:Glutathione; D002118:Calcium
keywords: 2,3,5-tris(glutathion-S-yl)hydroquinone; HK-2 cells; apoptosis-inducing factor; intracellular Ca2+; poly(ADP-ribose)polymerase-1; reactive oxygen species
references.citation: Trends Pharmacol Sci. 1999 Apr;20(4):171-81
references.pmid: 10322503
references.citation: J Immunol. 1998 Oct 1;161(7):3753-9
references.pmid: 9759901
references.citation: Inflammation. 1995 Jun;19(3):379-87
references.pmid: 7628865
references.citation: Ann N Y Acad Sci. 2008 Dec;1147:233-41
references.pmid: 19076445
references.citation: Methods Enzymol. 1997;280:221-30
references.pmid: 9211317
references.citation: Ann N Y Acad Sci. 1999;890:227-39
references.pmid: 10668429
references.citation: Am J Physiol Regul Integr Comp Physiol. 2000 Nov;279(5):R1834-40
references.pmid: 11049868
references.citation: Pharmacol Rev. 2002 Sep;54(3):375-429
references.pmid: 12223530
references.citation: Biochem Pharmacol. 1988 Oct 15;37(20):3967-74
references.pmid: 3142482
references.citation: Mol Pharmacol. 1999 Oct;56(4):824-33
references.pmid: 10496967
references.citation: Nat Med. 1999 Mar;5(3):314-9
references.pmid: 10086388
references.citation: Nat Rev Mol Cell Biol. 2008 May;9(5):378-90
references.pmid: 18414491
references.citation: Free Radic Res. 2003 Mar;37(3):331-9
references.pmid: 12688429
references.citation: Cell Mol Life Sci. 2006 Dec;63(24):3061-71
references.pmid: 17131054
references.citation: Toxicol Sci. 2012 Jul;128(1):103-14
references.pmid: 22523229
references.citation: Circ Res. 2007 Mar 30;100(6):914-22
references.pmid: 17332429
references.citation: EMBO J. 1999 Aug 16;18(16):4446-54
references.pmid: 10449410
references.citation: Mol Cell Biol. 2007 Jul;27(13):4844-62
references.pmid: 17470554
references.citation: Exp Cell Res. 1986 Jun;164(2):273-81
references.pmid: 2940104
references.citation: Proc Natl Acad Sci U S A. 1982 Nov;79(22):6842-6
references.pmid: 6817329
references.citation: Pflugers Arch. 2007 Dec;455(3):375-96
references.pmid: 17611770
references.citation: Science. 2002 Jul 12;297(5579):259-63
references.pmid: 12114629
references.citation: Biochemistry. 2004 Jan 13;43(1):210-6
references.pmid: 14705947
references.citation: Mol Pharmacol. 1988 Dec;34(6):829-36
references.pmid: 3200250
references.citation: J Cereb Blood Flow Metab. 1997 Nov;17(11):1143-51
references.pmid: 9390645
references.citation: J Biol Chem. 1986 Jan 15;261(2):965-9
references.pmid: 3941108
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18314-9
references.pmid: 17116881
references.citation: Mol Aspects Med. 2013 Dec;34(6):1046-65
references.pmid: 23290998
references.citation: Circ Res. 1998 Jul 13;83(1):85-94
references.pmid: 9670921
references.citation: J Cell Biol. 2000 Jul 24;150(2):293-307
references.pmid: 10908573
references.citation: J Exp Med. 1997 Oct 6;186(7):1041-9
references.pmid: 9314553
references.citation: Chem Biol Interact. 1991;77(1):1-23
references.pmid: 1983962
references.citation: Cancer Res. 2004 Dec 15;64(24):8960-7
references.pmid: 15604259
references.citation: Neurochem Int. 2007 Jan;50(1):203-10
references.pmid: 17052800
references.citation: Cell Mol Life Sci. 2011 Apr;68(8):1455-66
references.pmid: 20878536
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3059-64
references.pmid: 10077636
references.citation: Cardiovasc Drugs Ther. 2007 Aug;21(4):227-33
references.pmid: 17665295
references.citation: Chem Res Toxicol. 2001 Jan;14(1):25-33
references.pmid: 11170505
references.citation: Antioxid Redox Signal. 2008 Feb;10(2):179-206
references.pmid: 18020963
references.citation: Teratog Carcinog Mutagen. 1996;16(4):219-27
references.pmid: 9381409
references.citation: Leukemia. 2010 Apr;24(4):679-86
references.pmid: 20130602