Abstract
Under oxidative stress, poly(ADP-ribose) polymerase-1 (PARP-1) is activated and contributes to necrotic cell death through ATP depletion. On the other hand, oxidative stress is known to stimulate autophagy, and autophagy may act as either a cell death or cell survival mechanism. This study aims to explore the regulatory role of PARP-1 in oxidative stress-mediated autophagy and necrotic cell death. Here, we first show that hydrogen peroxide (H2O2) induces necrotic cell death in Bax−/− Bak−/− mouse embryonic fibroblasts through a mechanism involving PARP-1 activation and ATP depletion. Next, we provide evidence that autophagy is activated in cells exposed to H2O2. More importantly, we identify a novel autophagy signaling mechanism linking PARP-1 to the serine/threonine protein kinase LKB1-AMP-activated protein kinase (AMPK)–mammalian target of rapamycin (mTOR) pathway, leading to stimulation of autophagy. Finally, we demonstrate that autophagy plays a cytoprotective role in H2O2-induced necrotic cell death, as suppression of autophagy by knockdown of autophagy-related gene ATG5 or ATG7 greatly sensitizes H2O2-induced cell death. Taken together, these findings demonstrate a novel function of PARP-1: promotion of autophagy through the LKB1-AMPK–mTOR pathway to enhance cell survival in cells under oxidative stress.
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Abbreviations
- 3AB:
-
3-amino benzamide
- AMPK:
-
AMP-activated protein kinase
- ATG:
-
autophagy-related gene
- CHX:
-
cycloheximide
- CQ:
-
chloroquine
- DMEM:
-
Dulbecco's modified Eagle's medium
- ETO:
-
etoposide
- MEFs:
-
mouse embryonic fibroblasts
- MP:
-
methylpyruvate
- mTOR:
-
mammalian target of rapamycin
- PARP-1:
-
Poly(ADP-Ribose) Polymerase-1
- PI:
-
propidium iodide
- ROS:
-
reactive oxygen species
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Acknowledgements
We thank Drs. Emily Cheng, T Yoshimori and Koh Ono for reagents, and V Tergaonkar and ET Wong for helpful discussion and suggestions. Q Huang is supported by the Toxicology Program, Office of Life Science, NUS and YT Wu is supported by a NUS scholarship. The research work was also partly supported by research grants from the National Medical Research Council (NMRC) and Biomedical Research Council (BMRC), Singapore.
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Huang, Q., Wu, YT., Tan, HL. et al. A novel function of poly(ADP-ribose) polymerase-1 in modulation of autophagy and necrosis under oxidative stress. Cell Death Differ 16, 264–277 (2009). https://doi.org/10.1038/cdd.2008.151
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DOI: https://doi.org/10.1038/cdd.2008.151
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