Document Detail


Poly (ADP-ribose) polymerase activity regulates apoptosis in HeLa cells after alkylating DNA damage.
MedLine Citation:
PMID:  18376143     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Majority of chemotherapeutic agents inhibit tumor growth by inducing apoptosis or necrosis. The DNA alkylating agent, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), kills cells by necrosis through massive production of DNA strand breaks and subsequent over-activation of PARP. Inhibition of PARP, either through PARP1 genetic ablation or through small molecule PARP inhibitors, protected MNNG-induced cell death in certain cell types including MEF and primary cortical cultures. We report here that a potent PARP inhibitor, ABT-888, facilitates the induction of apoptotic cell death in HeLa cells treated with MNNG. Although the release of cytochrome c from mitochondria to cytosol was observed in HeLa cells treated with either MNNG alone or the combination of MNNG and ABT-888 (MNNG/ABT-888), apoptosis is observed only in HeLa cells treated with MNNG/ABT-888. Bcl-2 family proteins regulate the release of cytochrome c. Downregulation of Bax and Bak by their corresponding siRNAs or overexpression of Bcl-xl inhibited the release of cytochrome c from mitochondria to cytosol, and inhibited apoptosis induced by MNNG/ABT-888. Further examination indicates that ATP concentration is greatly reduced in HeLa cells treated with MNNG alone, but not in HeLa cells treated with MNNG/ABT-888. Reduction of ATP concentration by F0F1-ATP synthase inhibitor oligomycin A renders HeLa cells resistant to the apoptosis induction by treatment with MNNG/ABT-888. Unlike in HeLa cells, ABT-888 protected MNNG induced cell death in normal human fibroblasts. Our study provides evidence that PARP activity determines the fate of HeLa cells by regulating the level of ATP after treatment with MNNG.
Authors:
Xuesong Liu; Xu Luo; Yan Shi; Gui-Dong Zhu; Thomas Penning; Vincent L Giranda; Yan Luo
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Publication Detail:
Type:  Journal Article     Date:  2008-03-19
Journal Detail:
Title:  Cancer biology & therapy     Volume:  7     ISSN:  1555-8576     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2008 Jun 
Date Detail:
Created Date:  2008-08-19     Completed Date:  2008-11-18     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  934-41     Citation Subset:  IM    
Affiliation:
Department R47S, Cancer Research, Abbott Laboratories, Abbott Park, Illinois 60064, USA. xuesong.liu@abbott.com
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MeSH Terms
Descriptor/Qualifier:
Alkylating Agents / pharmacology
Animals
Apoptosis
Benzimidazoles / pharmacology
Cytochromes c / metabolism
DNA Damage*
Fibroblasts / metabolism
Gene Expression Regulation, Enzymologic*
Hela Cells
Humans
Methylnitronitrosoguanidine / pharmacology
Mice
NAD / chemistry
Oligomycins / pharmacology
Poly(ADP-ribose) Polymerases / metabolism*
Chemical
Reg. No./Substance:
0/2-((R)-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide; 0/Alkylating Agents; 0/Benzimidazoles; 0/Oligomycins; 53-84-9/NAD; 579-13-5/oligomycin A; 70-25-7/Methylnitronitrosoguanidine; 9007-43-6/Cytochromes c; EC 2.4.2.30/Poly(ADP-ribose) Polymerases
Comments/Corrections
Comment In:
Cancer Biol Ther. 2008 Jun;7(6):942-4   [PMID:  18720555 ]

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