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Nicotinamide- and caspase-mediated inhibition of poly(ADP-ribose) polymerase are associated with p53-independent cell cycle (G2) arrest and apoptosis

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Abstract

Poly(ADP-ribose) polymerase (PARP), which is activated by DNA strand breaks, is involved in DNA repair and replication but, during apoptosis, undergoes early caspase-mediated cleavage. Activation of programmed cell death in response to DNA damage may rely on functional p53 protein. Tumor cells are commonly deficient in this oncogene product resulting in resistance to many cytostatic drugs. Here we report that nicotinamide-induced inhibition of poly(ADP-ribosyl)ation and cytokine-induced nitric oxide production both result in a transient increase in p53 levels in pancreatic tumor RINm5F cells. These treatments also induce disruption of the mitochondrial membrane potential (ΔΨm), as revealed using the mitochondrial probe JC-1, followed by PARP cleavage and apoptosis all of which are inhibited by the anti-apoptotic protein Bcl-2. Moreover, PARP-inhibition by nicotinamide or 3-aminobenzamide induces apoptosis and/or cell cycle arrest at the G2 checkpoint in all of four tested tumor cell lines of both mesenchymal and epithelial origin including mouse NIH-3T3 cells and p53 deficient human HeLa and Jurkat cells. Bcl-2 counteracts cytokine-, but not nicotinamide-induced G2 arrest. These findings indicate that both chemical and caspase-mediated inhibition of PARP activity, possibly by interfering with DNA replication and repair, may promote a p53-independent G2 arrest and apoptosis.

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Authors and Affiliations

  1. Department of Medical Cell Biology, Uppsala University, S-751 23, Uppsala, Sweden

    Johan Saldeen, Linda Tillmar, Ella Karlsson & Nils Welsh

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  1. Johan Saldeen
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  2. Linda Tillmar
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  3. Ella Karlsson
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  4. Nils Welsh
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Saldeen, J., Tillmar, L., Karlsson, E. et al. Nicotinamide- and caspase-mediated inhibition of poly(ADP-ribose) polymerase are associated with p53-independent cell cycle (G2) arrest and apoptosis. Mol Cell Biochem 243, 113–122 (2003). https://doi.org/10.1023/A:1021651811345

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