Jaridonin-induced G2/M phase arrest in human esophageal cancer cells is caused by reactive oxygen species-dependent Cdc2-tyr15 phosphorylation via ATM-Chk1/2-Cdc25C pathway.
Jaridonin-induced G2/M phase arrest in human esophageal cancer cells is caused by reactive oxygen species-dependent Cdc2-tyr15 phosphorylation via ATM-Chk1/2-Cdc25C pathway.
复制标题
Jaridonin 诱导的人食管癌细胞 G2/M 期阻滞是由活性氧依赖性 Cdc2-tyr15 通过 ATM→Chk1/2→Cdc25C 途径磷酸化引起的
DOI：
10.1016/j.taap.2014.11.003
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发表时间：
2015-01-15
影响因子：
3.8
通讯作者：
Liu HM
中科院分区：
文献类型：
--
作者：
Ma YC;Su N;Shi XJ;Zhao W;Ke Y;Zi X;Zhao NM;Qin YH;Zhao HW;Liu HM
胡萝卜素是冬凌草中的一个新的二萜类化合物，已被证明通过G2/M期细胞周期阻滞抑制食管鳞状癌细胞(ESCC)的增殖。然而，其涉及的机制尚不完全清楚。在这项研究中，我们发现Jaridin对细胞周期的抑制与ATM在Ser1981和CDc2在Tyr15的磷酸化表达增加有关。灯盏花素还通过激活Chk1和Chk2使cdc25C的磷酸化增强，并增加了磷酸化的H_2A.X(Ser139)，这种磷酸化是ATM对DNA损伤的反应。此外，在NAC存在的情况下，Jaridamin介导的细胞周期停滞的改变显著减弱，暗示ROS参与了Jaridatin的作用。另一方面，ATM抑制剂的加入逆转了Jaridamin对ATM和Chk1/2的激活以及对CDc25C、Cdc2和H2A.X的磷酸化以及G2/M期的停滞。综上所述，这些发现证实了姜黄素诱导的人食道癌细胞细胞周期停滞与ROS介导的ATM-Chk1/2-CDc25C通路的激活有关。
Jaridonin, a novel diterpenoid from Isodon rubescens, has been shown previously to inhibit proliferation of esophageal squamous cancer cells (ESCC) through G2/M phase cell cycle arrest. However, the involved mechanism is not fully understood. In this study, we found that the cell cycle arrest by Jaridonin was associated with the increased expression of phosphorylation of ATM at Ser1981 and Cdc2 at Tyr15. Jaridonin also resulted in enhanced phosphorylation of Cdc25C via the activation of checkpoint kinases Chk1 and Chk2, as well as in increased phospho-H2A.X (Ser139), which is known to be phosphorylated by ATM in response to DNA damage. Furthermore, Jaridonin-mediated alterations in cell cycle arrest were significantly attenuated in the presence of NAC, implicating the involvement of ROS in Jaridonin's effects. On the other hand, addition of ATM inhibitors reversed Jaridonin-related activation of ATM and Chk1/2 as well as phosphorylation of Cdc25C, Cdc2 and H2A.X and G2/M phase arrest. In conclusion, these findings identified that Jaridonin-induced cell cycle arrest in human esophageal cancer cells is associated with ROS-mediated activation of ATM–Chk1/2–Cdc25C pathway.