Celastrol induces apoptosis and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells: an in vitro and in vivo study.
Celastrol induces apoptosis and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells: an in vitro and in vivo study.
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雷公藤红素通过人骨肉瘤细胞中 ROS/JNK 信号通路诱导细胞凋亡和自噬：一项体外和体内研究。
DOI：
10.1038/cddis.2014.543
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发表时间：
2015-01-22
影响因子：
9
通讯作者：
Ye ZM
中科院分区：
文献类型：
--
作者：
Li HY;Zhang J;Sun LL;Li BH;Gao HL;Xie T;Zhang N;Ye ZM
骨肉瘤是最常见的原发性骨恶性肿瘤，其长期生存率在过去几十年中一直处于停滞状态。南蛇藤酚是一种三萜类中药，对多种肿瘤有较强的抗肿瘤作用。然而，雷公藤红素对人骨肉瘤的作用及其机制仍有待阐明。我们在这里报道雷公藤红素可以通过引起G2/M期阻滞来抑制细胞增殖。暴露于雷公藤红素导致半胱天冬酶-3、-8和-9的活化，表明雷公藤红素通过外源性和内源性途径诱导细胞凋亡。雷公藤红素处理的细胞中发生自噬，如通过自噬体的形成和LC 3B-II的积累所证明的。雷公藤红素诱导的细胞死亡显着恢复自噬和凋亡抑制剂的组合。此外，抑制细胞凋亡增强自噬，而抑制自噬减少细胞凋亡。雷公藤红素还诱导JNK活化和ROS产生。JNK抑制剂可显著减弱雷公藤红素诱导的细胞凋亡和自噬，而ROS清除剂可完全逆转它们。ROS清除剂还阻止G2/M期阻滞和JNK磷酸化。更重要的是，我们发现雷公藤红素对原代骨肉瘤细胞具有类似的作用。最后，在体内，雷公藤红素抑制小鼠异种移植模型中的肿瘤生长。综上所述，我们的结果表明雷公藤红素通过ROS/JNK信号通路诱导人骨肉瘤细胞G2/M期阻滞，诱导细胞凋亡和自噬。因此，南蛇藤酚是一个很有前途的候选开发抗肿瘤药物靶向骨肉瘤。
Osteosarcoma is the most common primary malignant tumor of bone, the long-term survival of which has stagnated in the past several decades. Celastrol, a triterpene from traditional Chinese medicine, has been proved to possess potent anti-tumor effect on various cancers. However, the effect of celastrol on human osteosarcoma and the underlying mechanisms remains to be elucidated. We reported here that celastrol could inhibit cell proliferation by causing G2/M phase arrest. Exposure to celastrol resulted in the activation of caspase-3, -8, and -9, indicating that celastrol induced apoptosis through both extrinsic and intrinsic pathways. Autophagy occurred in celastrol-treated cells as evidenced by formation of autophagosome and accumulation of LC3B-II. The celastrol-induced cell death was remarkably restored by the combination of autophagy and apoptosis inhibitors. Furthermore, inhibition of apoptosis enhanced autophagy while suppression of autophagy diminished apoptosis. Celastrol also induced JNK activation and ROS generation. The JNK inhibitor significantly attenuated celastrol-triggered apoptosis and autophagy while ROS scavenger could completely reverse them. The ROS scavenger also prevented G2/M phase arrest and phosphorylation of JNK. Importantly, we found that celastrol had the similar effects on primary osteosarcoma cells. Finally, in vivo, celastrol suppressed tumor growth in the mouse xenograft model. Taken together, our results revealed that celastrol caused G2/M phase arrest, induced apoptosis and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells. Celastrol is therefore a promising candidate for development of antitumor drugs targeting osteosarcoma.