Increased oxidative stress mediates the antitumor effect of PARP inhibition in ovarian cancer
Dong Hou,
Zhaojian Liu,
Xiuhua Xu,
Qiao Liu,
Xiyu Zhang,
Beihua Kong,
Jian-Jun Wei,
Yaoqin Gong,
Changshun Shao
Affiliations
Dong Hou
Key Laboratory of Experimental Teratology, Ministry of Education/Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China
Zhaojian Liu
Department of Cell Biology, Shandong University School of Medicine, Jinan, Shandong 250012, China
Xiuhua Xu
Key Laboratory of Experimental Teratology, Ministry of Education/Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China
Qiao Liu
Key Laboratory of Experimental Teratology, Ministry of Education/Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China
Xiyu Zhang
Key Laboratory of Experimental Teratology, Ministry of Education/Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China
Beihua Kong
Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
Jian-Jun Wei
Department of Pathology, Northwestern University School of Medicine, Chicago, IL, USA
Yaoqin Gong
Key Laboratory of Experimental Teratology, Ministry of Education/Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China
Changshun Shao
Key Laboratory of Experimental Teratology, Ministry of Education/Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China; The First Affiliated Hospital of Soochow University and State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, 199 Ren Ai Road, Suzhou, Jiangsu 215123, China; Corresponding author at: The First Affiliated Hospital of Soochow University and State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, 199 Ren Ai Road, Suzhou, Jiangsu 215123, China.
PARP inhibitors have been widely tested in clinical trials, especially for the treatment of breast cancer and ovarian cancer, and were shown to be highly successful. Because PARP primarily functions in sensing and repairing DNA strand breaks, the therapeutic effect of PARP inhibition is generally believed to be attributed to impaired DNA repair. We here report that oxidative stress is also increased by PARP inhibition and mediates the antitumor effect. We showed that PARP1 is highly expressed in specimens of high grade serous ovarian carcinoma and its activity is required for unperturbed proliferation of ovarian cancer cells. Inhibition or depletion of PARP leads to not only an increase in DNA damage, but also an elevation in the levels of reactive oxygen species (ROS). Importantly, antioxidant N-acetylcysteine (NAC) significantly attenuated the induction of DNA damage and the perturbation of proliferation by PARP inhibition or depletion. We further showed that NADPH oxidases 1 and 4 were significantly upregulated by PARP inhibition and were partially responsible for the induction of oxidative stress. Depletion of NOX1 and NOX4 partially rescued the growth inhibition of PARP1-deficient tumor xenografts. Our findings suggest that in addition to compromising the repair of DNA damage, PARP inhibition or depletion may exert extra antitumor effect by elevating oxidative stress in ovarian cancer cells. Keywords: PARP1, Oxidative stress, NADPH oxidases, Ovarian cancer
