PARP-1 is involved in autophagy induced by DNA damage

作者：José Antonio Muñoz‐Gámez, José Manuel Rodríguez-Vargas, R. Quiles, Rocío Aguilar‐Quesada, David Martín‐Oliva, Gilbert de Murcia, Josiane Ménissier de Murcia, Antonio Almendros-Ruiz, Mariano Ruiz de Almodóvar, Francisco Javier Oliver · 发表于：Autophagy · 年份：2009 · DOI：10.4161/auto.5.1.7272 · 被引用次数：239 · 研究领域：Autophagy in Disease and Therapy、PARP inhibition in cancer therapy、Cell death mechanisms and regulation

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.