Resveratrol sequentially induces replication and oxidative stresses to drive p53-CXCR2 mediated cellular senescence in cancer cells.
Resveratrol sequentially induces replication and oxidative stresses to drive p53-CXCR2 mediated cellular senescence in cancer cells.
复制标题
白藜芦醇依次诱导复制和氧化应激，驱动癌细胞中 p53-CXCR2 介导的细胞衰老
DOI：
10.1038/s41598-017-00315-4
复制
发表时间：
2017-03-16
影响因子：
4.6
通讯作者：
Shao C
中科院分区：
文献类型：
--
作者：
Li B;Hou D;Guo H;Zhou H;Zhang S;Xu X;Liu Q;Zhang X;Zou Y;Gong Y;Shao C
白藜芦醇(RSV)既可以作为抗氧化剂，也可以作为促氧化剂，这取决于具体情况。RSV治疗的癌细胞可能会经历复制压力，这可能会导致细胞衰老或凋亡。虽然氧化应激和复制应激都可能介导RSV的抗增殖作用，但它们在多大程度上促进了RSV的受损增殖尚不清楚。我们在此报告复制和氧化应激在RSV治疗的癌细胞中介导细胞衰老的作用的研究。呼吸道合胞病毒以剂量依赖的方式诱导U2OS和A549癌细胞及正常人成纤维细胞发生S期阻滞和细胞衰老。我们观察到，核苷显著减轻RSV诱导的复制应激和DNA损伤反应，从而延缓细胞衰老。而活性氧自由基(ROS)的升高也介导了RSV的延缓衰老作用，但这种作用发生在S时相停止之后。然而，RSV诱导的ROS不依赖于S时相的阻断，而实际上加强了后者。我们还证明了P53-CXCR2轴在调节RSV诱导的衰老中的关键作用。有趣的是，CXCR2也起到了细胞凋亡的屏障作用。总而言之，我们的结果为RSV诱导的压力及其细胞后果的生物学提供了更多的见解。
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.