Oridonin induced apoptosis through Akt and MAPKs signaling pathways in human osteosarcoma cells
Oridonin induced apoptosis through Akt and MAPKs signaling pathways in human osteosarcoma cells
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冬凌草甲素通过 Akt 和 MAPKs 信号通路诱导人骨肉瘤细胞凋亡
DOI：
10.4161/cbt.6.2.3621
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发表时间：
2007-02-01
影响因子：
3.6
通讯作者：
Zhou, Jia-Guo
中科院分区：
文献类型：
--
作者：
Jin, Song;Shen, Jing-nan;Zhou, Jia-Guo
先前的研究表明，冬凌草甲素，一种从冬凌草中分离的二萜类化合物，能够抑制多种细胞类型的增殖和诱导凋亡。但其机制仍然知之甚少。本研究探讨了冬凌草甲素对人骨肉瘤细胞的诱导凋亡作用及其作用机制。我们的研究结果表明，冬凌草甲素诱导U2 OS，MG 63和SaOS-2骨肉瘤细胞株的增殖抑制和凋亡激活的浓度和时间依赖性。冬凌草甲素诱导细胞色素c的释放，并伴有caspase-9、caspase-3的激活和聚腺苷二磷酸核糖聚合酶（PARP）的裂解。这些事件均被一种通用的半胱天冬酶抑制剂z-VAD-fatase抑制。冬凌草甲素处理使组成型活性AKT、FOXO转录因子和糖原合成酶激酶3（GSK 3）去磷酸化。另外，冬凌草甲素还能降低ERK的磷酸化水平，增加p38 MAPK和JNK的磷酸化水平。此外，冬凌草甲素处理下调骨肉瘤细胞凋亡抑制蛋白（IAP）的表达。总之，我们的研究结果表明，冬凌草甲素能够抑制Akt和ERK，并激活p38 MAPK和JNK信号通路在骨肉瘤细胞引起的增殖抑制和诱导线粒体和caspase依赖的凋亡。
Previous studies have shown that oridonin, a diterpenoid isolated from Rabdosia rubescens, was able to inhibit proliferation and induce apoptosis in several cell types. But the mechanisms remain poorly understood. In this study, we investigated the apoptosis-inducing effect and mechanisms of action of oridonin in human osteosarcoma cells. Our results demonstrated that oridonin induced concentration- and time-dependent suppression of proliferation and activation of apoptosis in U2OS, MG63 and SaOS-2 osteosarcoma cell lines. Oridonin induced the release of cytochrome c accompanied by activation of caspase-9, caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). These events were all inhibited by z-VAD-fmk, a universal inhibitor of caspases. Oridonin treatment dephosphorylated constitutively active AKT, FOXO transcription factor, and glycogen synthase kinase 3 (GSK3). In addition, oridonin decreased the phosphorylation of ERK and increased the phosphorylation of p38 MAPK and JNK. Furthermore, oridonin treatment down-regulated the expression of the inhibitor of apoptosis protein(IAP) in osteosarcoma cells. All together, our results suggested that oridonin is able to inactivate Akt and ERK and activate p38 MAPK and JNK signalling pathways in osteosarcoma cells causing the suppression of proliferation and induction of mitochondria- and caspase-dependent apoptosis.