期刊
AUTOPHAGY
卷 5, 期 1, 页码 61-74出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/auto.5.1.7272
关键词
autophagy; DNA damage; PARP-1; energy depletion; Beclin 1; ATG-5; mTOR; doxorubicin
类别
资金
- FIS [00/0948, G03/152, CP03/00142]
- SAF [SAF:2003-01217, SAF:2006-01094, SAF:2001-3533]
- Fundacion La Caixa [BM06-219-0, PO7-CTS-0239]
- Ministerio de Educacion y Ciencia
- Ciberehd
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 1 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.
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