Zerumbone, a bioactive sesquiterpene, induces G2/M cell cycle arrest and apoptosis in leukemia cells via a Fas- and mitochondria-mediated pathway
Zerumbone, a bioactive sesquiterpene, induces G2/M cell cycle arrest and apoptosis in leukemia cells via a Fas- and mitochondria-mediated pathway
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DOI：
10.1111/j.1349-7006.2006.00362.x
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发表时间：
2007-01-01
期刊：
影响因子：
5.7
通讯作者：
Kizaki, Masahiro
中科院分区：
文献类型：
--
作者：
Xian, Mingji;Ito, Keisuke;Kizaki, Masahiro
我们在此首次证明，Zerumbone (ZER)（一种天然环状倍半萜烯）通过诱导 G2/M 细胞周期停滞，然后用 10 μM 的 IC50 诱导细胞凋亡，显着抑制几种白血病细胞系中早幼粒细胞白血病 NB4 细胞的增殖，但不能抑制人脐静脉内皮细胞 (HUVEC) 的增殖。用生长抑制浓度的 ZER 处理 NB4 细胞会导致 G2/M 细胞周期停滞，这与 Cyclin B1 蛋白的下降有关，但与 ATM/Chk1/Chk2 的磷酸化有关。此外，ZER 诱导 Cdc25C 在 Thr48 残基处和 Cdc2 在 Thr14/Tyr15 残基处磷酸化。此外，ZER 诱导的 NB4 细胞凋亡是由 Fas (CD95)/Fas 配体 (CD95L) 的表达以及 caspase-8 的激活引发的。 ZER 还被发现能诱导 Bid 的裂解，Bid 是一种已知将 Fas/CD95 细胞死亡受体与线粒体凋亡途径连接起来的介质。 ZER 还诱导 Bax 和 Mcl-1 蛋白的裂解，但不诱导 Bcl-2 或 Bcl-X-L 的裂解。 ZER 诱导的细胞凋亡与线粒体跨膜电位的丧失以及 caspase-3 和 -9 的激活相关，导致蛋白水解聚（ADP-核糖）聚合酶（PARP）的降解。 ZER 还触发细胞色素 c 释放到细胞质中。拮抗性抗 Fas 抗体 ZB4 和泛半胱天冬酶抑制剂 Z-VAD 均抑制 ZER 诱导的 NB4 细胞凋亡。总而言之，ZER 是白血病细胞中的细胞凋亡诱导剂，可特异性触发 Fas/CD95 和线粒体介导的细胞凋亡信号通路。
We demonstrated here for the first time that zerumbone (ZER), a natural cyclic sesquiterpene, significantly suppressed the proliferation of promyelocytic leukemia NB4 cells among several leukemia cell lines, but not human umbilical vein endothelial cells (HUVECs), by inducing G2/M cell cycle arrest followed by apoptosis with 10 mu M of IC50. Treatment of NB4 cells with growth-suppressive concentrations of ZER resulted in G2/M cell cycle arrest that was associated with a decline of Cyclin B1 protein, but with the phosphorylation of ATM/Chk1/Chk2. In addition, ZER induced the phosphorylation of Cdc25C at the Thr48 residue and Cdc2 at the Thr14/Tyr15 residues. Furthermore, ZER-induced apoptosis in NB4 cells was initiated by the expression of Fas (CD95)/Fas Ligand (CD95L), concomitant with the activation of caspase-8. ZER was also found to induce the cleavage of Bid, a mediator that is known to connect the Fas/CD95 cell death receptor to the mitochondrial apoptosis pathway. ZER also induced the cleavage of Bax and Mcl-1 proteins, but not Bcl-2 or Bcl-X-L. ZER-induced apoptosis took place in association with a loss of the mitochondrial transmembrane potential as well as the activation of caspase-3 and -9, resulting in the degradation of the proteolytic poly (ADP-ribose) polymerase (PARP). ZER also triggered a release of cytochrome c into the cytoplasm. Both antagonistic anti-Fas antibody ZB4 and pan-caspase inhibitor Z-VAD inhibited ZER-induced apoptosis in NB4 cells. Taken together, ZER is an inducer of apoptosis in leukemic cells that specifically triggers the Fas/CD95- and mitochondria-mediated apoptotic signaling pathway.