Oxidative stress response results in increased p21WAF1/CIP1 degradation in cystic fibrosis lung epithelial cells |
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| Authors: | Boncoeur Emilie Tabary Olivier Bonvin Elise Muselet Celine Fritah Asmaa Lefait Emilie Redeuilh Gerard Clement Annick Jacquot Jacky Henrion-Caude Alexandra |
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| Affiliation: | 1. Inserm U719, Université Pierre et Marie Curie, Hôpital Saint-Antoine, 184 rue du Fg St Antoine, Bâtiment Kourilsky, 75571 Paris Cedex 12, France;2. Inserm U673, Université Pierre et Marie Curie, Hôpital Saint-Antoine, Bâtiment Kourilsky, 75571 Paris Cedex 12, France;1. Hasselt University, Transportation Research Institute (IMOB), Wetenschapspark 5, bus 6, BE-3590 Diepenbeek, Belgium;2. Faculty of Applied Engineering Sciences, Agoralaan—building H, BE-3590 Diepenbeek, Belgium;1. Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, 3010, Australia;2. Gynaecology Research Centre, Royal Women’s Hospital, Parkville, Victoria, 3052, Australia;1. College of Food Science and Engineering/Collaborative Innovation Center for Modern Grain Circulation and Safety/Key Laboratory of Grains and Oils Quality Control and Processing, Nanjing University of Finance and Economics, Nanjing 210023, People’s Republic of China;2. College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, People’s Republic of China;3. College of Food Science and Technology, Henan University of Technology, Zhengzhou 450001, People’s Republic of China |
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| Abstract: | Lung epithelium in cystic fibrosis (CF) patients is characterized by structural damage and altered repair due to oxidative stress. To gain insight into the oxidative stress-related damage in CF, we studied the effects of hyperoxia in CF and normal lung epithelial cell lines. In response to a 95% O2 exposure, both cell lines exhibited increased reactive oxygen species. Unexpectedly, the cyclin-dependent kinase inhibitor p21WAF1/CIP1 protein was undetectable in CF cells under hyperoxia, contrasting with increased levels of p21WAF1/CIP1 in normal cells. In both cell lines, exposure to hyperoxia led to S-phase arrest. Apoptotic features including nuclear condensation, DNA laddering, Annexin V incorporation, and elevated caspase-3 activity were not readily observed in CF cells in contrast to normal cells. Interestingly, treatment of hyperoxia-exposed CF cells with two proteasome inhibitors, MG132 and lactacystin, restored p21WAF1/CIP1 protein and was associated with an increase of caspase-3 activity. Moreover, transfection of p21WAF1/CIP1 protein in CF cells led to increased caspase-3 activity and was associated with increased apoptotic cell death, specifically under hyperoxia. Taken together, our data suggest that modulating p21WAF1/CIP1 degradation may have the therapeutic potential of reducing lung epithelial damage related to oxidative stress in CF patients. |
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