The molecular "Jekyll and Hyde" duality of PARP1 in cell death and cell survival

Hassa, Paul O.

doi:10.2741/3232

Cited by 54 publications

(40 citation statements)

References 349 publications

(783 reference statements)

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“…Genotoxic stresses, such as oxidants and alkylating agents, have long been known to cause necrotic cell death that is associated with an overstimulation of PARP1 (Hassa, 2009). Moreover, ischemia/ reperfusion-induced myocardial and cerebral necrosis is markedly attenuated by genetic inhibition of PARP1 (Zingarelli et al, 1998;Li et al, 2010).…”

Section: Introductionmentioning

confidence: 94%

PARP1-mediated necrosis is dependent on parallel JNK and Ca2+/calpain pathways

Douglas

Baines

2014

Journal of Cell Science

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Poly(ADP-ribose) polymerase-1 (PARP1) is a nuclear enzyme that can trigger caspase-independent necrosis. Two main mechanisms for this have been proposed: one involving RIP1 and JNK kinases and mitochondrial permeability transition (MPT), the other involving calpain-mediated activation of Bax and mitochondrial release of apoptosis-inducing factor (AIF). However, whether these two mechanisms represent distinct pathways for PARP1-induced necrosis, or whether they are simply different components of the same pathway has yet to be tested. Mouse embryonic fibroblasts (MEFs) were treated with either N-methyl-N9-nitro-N-nitrosoguanidine (MNNG) or b-Lapachone, resulting in PARP1-dependent necrosis. This was associated with increases in calpain activity, JNK activation and AIF translocation. JNK inhibition significantly reduced MNNGand b-Lapachone-induced JNK activation, AIF translocation, and necrosis, but not calpain activation. In contrast, inhibition of calpain either by Ca 2+ chelation or knockdown attenuated necrosis, but did not affect JNK activation or AIF translocation. To our surprise, genetic and/or pharmacological inhibition of RIP1, AIF, Bax and the MPT pore failed to abrogate MNNG-and b-Lapachone-induced necrosis. In conclusion, although JNK and calpain both contribute to PARP1-induced necrosis, they do so via parallel mechanisms.

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Section: Introductionmentioning

confidence: 94%

PARP1-mediated necrosis is dependent on parallel JNK and Ca2+/calpain pathways

Douglas

Baines

2014

Journal of Cell Science

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“…Such a decrease suggested the onset of processes counteracting sustained PARP1 activation and the subsequent PARP1-dependent necrotic cell death [34]. As PARP1 cleavage by caspase 3 to a non-functional 89 kDa peptide is known to be crucial for the shift from the necrotic to the apoptotic program, we evaluated the presence of this proteolytic fragment in SR141716-treated…”

Section: Role Of Parp1 In Sr141716-induced Leukemia Cell Deathmentioning

confidence: 99%

Rimonabant-induced apoptosis in leukemia cell lines: Activation of caspase-dependent and -independent pathways

Gallotta¹,

Nigro²,

Cotugno³

et al. 2010

Biochemical Pharmacology

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Rimonabant (SR141716), a cannabinoid CB1 receptor antagonist known for anti-obesity activity, has more recently been shown to inhibit tumor cell growth. Here we demonstrated the anti-tumor potential of SR141716 in leukemia-derived cell lines and its low toxicity in normal cells (PBMC). SR141716(1-20 M range of doses) reduced Jurkat and U937 cell number by activating death signals as well as affecting cell cycle progression. The most prominent response in U937 to SR141716 was a G 0 /G 1 block, while in Jurkat cells there was activation of cell death processes.SR141716-treated cells exhibited the morphological and biochemical features of apoptosis and to some extent necrosis. Apoptotic mode of cell death was confirmed in both cell lines by analysis of cell morphology, phosphatidylserine exposure and DNA fragmentation. Moreover, the drug was found to induce an early and robust mitochondrial membrane depolarization. In Jurkat cells the apoptotic process was typically caspase-dependent, while in U937 caspase-independent pathways were also activated. The contribution of PARP activation to SR141716-induced apoptosis in U937 was suggested by protein PARylation, AIF release and apoptosis reversal by PARP inhibitors.Moreover, SR141716 negatively modulated, especially in U937, the PI3K/AKT pathways. In conclusion, our data indicate that SR141716 elicits alternative response and/or cell death pathways depending on the cell type affected.

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“…The capability to prevent hypoxia-or DNA damage-induced cell death despite high proliferative activity is a crucial characteristic of cancer cells (16). NAD þ plays a key role as a substrate and cofactor maintaining cellular integrity under these conditions.…”

Section: Introductionmentioning

confidence: 99%

The Endogenous Tryptophan Metabolite and NAD+ Precursor Quinolinic Acid Confers Resistance of Gliomas to Oxidative Stress

et al. 2013

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Quinolinic acid is a product of tryptophan degradation and may serve as a precursor for NAD þ , an important enzymatic cofactor for enzymes such as the DNA repair protein PARP. Pathologic accumulation of quinolinic acid has been found in neurodegenerative disorders including Alzheimer and Huntington disease, where it is thought to be toxic for neurons by activating the N-methyl-D-aspartate (NMDA) receptor and inducing excitotoxicity. Although many tumors including gliomas constitutively catabolize tryptophan, it is unclear whether quinolinic acid is produced in gliomas and whether it is involved in tumor progression. Here, we show that quinolinic acid accumulated in human gliomas and was associated with a malignant phenotype. Quinolinic acid was produced by microglial cells, as expression of the quinolinic acid-producing enzyme 3-hydroxyanthranilate oxygenase (3-HAO) was confined to microglia in glioma tissue. Human malignant glioma cells, but not nonneoplastic astrocytes, expressed quinolinic acid phosphoribosyltransferase (QPRT) to use quinolinic acid for NAD þ synthesis and prevent apoptosis when de novo NAD þ synthesis was blocked.Oxidative stress, temozolomide, and irradiation induced QPRT in glioma cells. QPRT expression increased with malignancy. In recurrent glioblastomas after radiochemotherapy, QPRT expression was associated with a poor prognosis in two independent datasets. Our data indicate that neoplastic transformation in astrocytes is associated with a QPRT-mediated switch in NAD þ metabolism by exploiting microglia-derived quinolinic acid as an alternative source of replenishing intracellular NAD þ pools. The elevated levels of QPRT expression increase resistance to oxidative stress induced by radiochemotherapy, conferring a poorer prognosis. These findings have implications for therapeutic approaches inducing intracellular NAD þ depletion, such as alkylating agents or direct NAD þ synthesis inhibitors, and identify QPRT as a potential therapeutic target in malignant gliomas. Cancer Res; 73(11); 3225-34. Ó2013 AACR.

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The molecular "Jekyll and Hyde" duality of PARP1 in cell death and cell survival

Cited by 54 publications

References 349 publications

PARP1-mediated necrosis is dependent on parallel JNK and Ca2+/calpain pathways

PARP1-mediated necrosis is dependent on parallel JNK and Ca2+/calpain pathways

Rimonabant-induced apoptosis in leukemia cell lines: Activation of caspase-dependent and -independent pathways

The Endogenous Tryptophan Metabolite and NAD+ Precursor Quinolinic Acid Confers Resistance of Gliomas to Oxidative Stress

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