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Poly (ADP-ribose) polymerase activity regulates apoptosis in HeLa cells after alkylating DNA damage
| Content Provider | Scilit |
|---|---|
| Author | Liu, Xuesong Luo, Xu Shi, Yan Yan Zhu, Gui-Dong Penning, Thomas Giranda, Vincent L. Luo, Yan |
| Copyright Year | 2008 |
| Description | 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. Down-regulation of Bax and Bak by their corresponding siRNAs or over-expression 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. |
| Related Links | https://www.tandfonline.com/doi/pdf/10.4161/cbt.7.6.5933?needAccess=true |
| Ending Page | 941 |
| Page Count | 8 |
| Starting Page | 934 |
| ISSN | 15384047 |
| e-ISSN | 15558576 |
| DOI | 10.4161/cbt.7.6.5933 |
| Journal | Cancer Biology & Therapy |
| Issue Number | 6 |
| Volume Number | 7 |
| Language | English |
| Publisher | Informa UK Limited |
| Publisher Date | 2008-06-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: Cancer Biology & Therapy Biochemistry and Molecular Biology Cell Death Hela Cells Regulates Protected Mnng Induced Cell Apoptosis Induced Mnng Induced |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cancer Research Pharmacology Molecular Medicine Oncology |
