Abstract
Autophagy is a lysosome-dependent degradative pathway frequently activated in tumor cells treated with chemotherapy or radiation. PARP-1 has been implicated in different pathways leading to cell death and its inhibition potentiates chemotherapy-induced cell death. Whether PARP-1 participates in the cell's decision to commit to autophagy following DNA damage is still not known. To address this issue PARP-1 wild-type and deficient cells have been treated with a dose of doxorubicin that induces autophagy. Electron microscopy examination and GFP-LC3 transfection revealed autophagic vesicles and increased expression of genes involved in autophagy (bnip-3, cathepsin b and l and beclin-1) in wild-type cells treated with doxo but not in parp-1(-/-) cells or cells treated with a PARP inhibitor. Mechanistically the lack of autophagic features in PARP-1 deficient/PARP inhibited cells is attributed to prevention of ATP and NAD(+) depletion and to the activation of the key autophagy regulator mTOR. Pharmacological or genetical inhibition of autophagy results in increased cell death, suggesting a protective role of autophagy induced by doxorubicin. These results suggest that autophagy might be cytoprotective during the response to DNA damage and suggest that PARP-1 activation is involved in the cell's decision to undergo autophagy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Naphthylamine / analogs & derivatives
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1-Naphthylamine / pharmacology
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3T3 Cells
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Adenosine Triphosphate / deficiency
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Animals
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Apoptosis / drug effects
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Apoptosis Regulatory Proteins
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Autophagy* / drug effects
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Autophagy* / genetics
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Autophagy-Related Protein 5
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Beclin-1
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Cell Survival / drug effects
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DNA Damage*
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Doxorubicin / pharmacology
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Enzyme Activation / drug effects
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Gene Deletion
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Mice
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Microtubule-Associated Proteins / metabolism
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Mitochondria / drug effects
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Mitochondria / enzymology
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Mitochondria / ultrastructure
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Models, Biological
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NAD / deficiency
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Naphthalimides / pharmacology
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Necrosis / enzymology
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Poly(ADP-ribose) Polymerase Inhibitors
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Poly(ADP-ribose) Polymerases / metabolism*
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Protein Kinases / metabolism
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Proteins / metabolism
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Quinolones / pharmacology
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Subcellular Fractions / drug effects
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Subcellular Fractions / metabolism
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TOR Serine-Threonine Kinases
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Up-Regulation / drug effects
Substances
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Apoptosis Regulatory Proteins
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Atg5 protein, mouse
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Autophagy-Related Protein 5
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Beclin-1
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Becn1 protein, mouse
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Map1lc3b protein, mouse
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Microtubule-Associated Proteins
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Naphthalimides
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Poly(ADP-ribose) Polymerase Inhibitors
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Proteins
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Quinolones
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NAD
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4-amino-1,8-naphthalimide
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Doxorubicin
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Adenosine Triphosphate
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1-Naphthylamine
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Poly(ADP-ribose) Polymerases
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Protein Kinases
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mTOR protein, mouse
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TOR Serine-Threonine Kinases