title: Resveratrol sequentially induces replication and oxidative stresses to drive p53-CXCR2 mediated cellular senescence in cancer cells.
abstract: Resveratrol (RSV) acts either as an antioxidant or a pro-oxidant depending on contexts. RSV-treated cancer cells may experience replication stress that can lead to cellular senescence or apoptosis. While both oxidative and replication stresses may mediate the anti-proliferation effect of RSV, to what extent each contributes to the impaired proliferation in response to RSV remains uncharacterized. We here report the study of the roles of replication and oxidative stresses in mediating cellular senescence in cancer cells treated with RSV. RSV induced S-phase arrest and cellular senescence in a dose-dependent manner in U2OS and A549 cancer cells as well as in normal human fibroblasts. We observed that nucleosides significantly alleviated RSV-induced replication stress and DNA damage response, and consequently attenuating cellular senescence. While the elevation of reactive oxygen species (ROS) also mediated the pro-senescent effect of RSV, it occurred after S-phase arrest. However, the induction of ROS by RSV was independent of S-phase arrest and actually reinforced the latter. We also demonstrated a critical role of the p53-CXCR2 axis in mediating RSV-induced senescence. Interestingly, CXCR2 also functioned as a barrier to apoptosis. Together, our results provided more insights into the biology of RSV-induced stress and its cellular consequences.
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China.
authors.forename: Boxuan
authors.initials: B
authors.lastname: Li
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Hou
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Guo
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China.
authors.forename: Haibin
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China.
authors.forename: Shouji
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Xu
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China.
authors.forename: Xiyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China.
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China.
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, 250012, China. shaochangshun@sdu.edu.cn.|Department of Genetics/Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, 08854, USA. shaochangshun@sdu.edu.cn.
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
mesh_terms: D000072283:A549 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence; D004261:DNA Replication / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000235:genetics* / Q000378:metabolism; D000077185:Resveratrol; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D023063:Receptors, Interleukin-8B; D013267:Stilbenes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077185:Resveratrol