title: Induction of ROS-independent DNA damage by curcumin leads to G2/M cell cycle arrest and apoptosis in human papillary thyroid carcinoma BCPAP cells.
abstract: Previously we found that curcumin, the active constituent of dietary spice turmeric, showed potent inhibitory effects on the cell growth of thyroid cancer cells. However, the detailed anti-cancer mechanism of curcumin is still unknown. In this study, we have reported that curcumin induces significant DNA damage in human papillary thyroid carcinoma BCPAP cells in a dose-dependent manner as evidenced by the upregulated phosphorylation of H2A.X at Ser139, which was further confirmed by the long tails in the comet assay and the increase in the number of TUNEL-positive cells. Subsequently, curcumin treatment caused a significant accumulation of cells at the G2/M phase that eventually resulted in a caspase-dependent apoptosis in BCPAP cells. DNA agarose gel electrophoresis revealed that curcumin-induced DNA damage in BCPAP cells was independent of DNA conformational change. Pretreatment with reactive oxygen species (ROS) scavengers failed to block the phosphorylation of H2A.X, suggesting the non-involvement of ROS in curcumin-mediated DNA damage. Interestingly, ATM/ATR activation by curcumin induced phosphorylation of Chk2 (Thr68) followed by that of Cdc25C (Ser216) and Cdc2 (Tyr15), and Cyclin B1 accumulation. In addition, the ATM-specific inhibitor KU-55933 reversed curcumin-induced phosphorylation of H2A.X. These results collectively show that curcumin treatment induced the DNA damage response via triggering an ATM-activated Chk2-Cdc25C-Cdc2 signaling pathway. These observations provide novel mechanisms and potential targets for the better understanding of the anti-cancer mechanisms of curcumin.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China. yangsun@nju.edu.cn molpharm@163.com and Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu, China. yuhuixin@jsinm.org.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu, China. yuhuixin@jsinm.org.
authors.forename: Xian
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu, China. yuhuixin@jsinm.org.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu, China. yuhuixin@jsinm.org.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Bao
authors.affiliation: Department of Endocrinology & Metabolism and Institute of Endocrinology, the First Hospital of China Medical University, Shenyang, Liaoning, China.
authors.forename: Haixia
authors.initials: H
authors.lastname: Guan
authors.affiliation: State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Lu
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu, China. yuhuixin@jsinm.org.
authors.forename: Huixin
authors.initials: H
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China. yangsun@nju.edu.cn molpharm@163.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China. yangsun@nju.edu.cn molpharm@163.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors; D002291:Carcinoma, Papillary / Q000188:drug therapy* / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D011753:Pyrones / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D000972:Antineoplastic Agents, Phytogenic; D009025:Morpholines; D011753:Pyrones; D017382:Reactive Oxygen Species; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D003474:Curcumin