Antitumor activity of Raddeanin A is mediated by Jun amino‐terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma
Antitumor activity of Raddeanin A is mediated by Jun amino‐terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma
复制标题
DOI：
10.1111/cas.14008
复制
发表时间：
2019-04
期刊：
影响因子：
5.7
通讯作者：
Zhuoying Wang;Jiakang Shen;Wei Sun;Tao Zhang;D. Zuo;Hongsheng Wang;Gangyang Wang;Jing Xu;
中科院分区：
文献类型：
--
作者：
Zhuoying Wang;Jiakang Shen;Wei Sun;Tao Zhang;D. Zuo;Hongsheng Wang;Gangyang Wang;Jing Xu;
骨肉瘤是最常见的原发性骨恶性肿瘤。海葵苷A （Raddeanin A， RA）是从传统中药海葵中提取的一种具有抗肿瘤活性的齐墩烷型三萜皂苷。然而，类风湿关节炎对骨肉瘤的影响尚不清楚。在本研究中，我们发现RA在体外和体内以剂量和时间依赖的方式抑制骨肉瘤细胞的增殖和诱导细胞凋亡。RA治疗导致活性氧（ROS）产生过多，JNK和ERK1/2活化。通过激活caspase‐3、caspase‐8、caspase‐9和多ADP核糖聚合酶（PARP）裂解来评估凋亡诱导。ROS清除剂谷胱甘肽（GSH）、JNK SP600125药理学抑制剂或shRNA特异性下调JNK可显著恢复RA诱导的细胞死亡。此外，RA在人骨肉瘤中抑制信号换能器和转录激活因子3 （STAT3）的激活，GSH、SP600125和JNK‐shRNA可恢复这种抑制。进一步研究表明，JNK敲除后STAT3磷酸化水平升高。在胫骨异种移植肿瘤模型中，类风湿关节炎诱导骨肉瘤凋亡，并显著抑制肿瘤生长。综上所述，我们的研究结果表明，RA通过调节JNK/c‐Jun和STAT3信号通路抑制人骨肉瘤的增殖并诱导细胞凋亡。因此，类风湿关节炎可能是一种很有前途的骨肉瘤干预抗肿瘤药物。
Osteosarcoma is the most common primary malignant bone tumor. Raddeanin A (RA) is an active oleanane‐type triterpenoid saponin extracted from the traditional Chinese herb Anemone raddeana Regel that exerts antitumor activity against several cancer types. However, the effect of RA on osteosarcoma remains unclear. In the present study, we showed that RA inhibited proliferation and induced apoptosis of osteosarcoma cells in a dose‐ and time‐dependent way in vitro and in vivo. RA treatment resulted in excessive reactive oxygen species (ROS) generation and JNK and ERK1/2 activation. Apoptosis induction was evaluated by the activation of caspase‐3, caspase‐8, and caspase‐9 and poly‐ADP ribose polymerase (PARP) cleavage. RA‐induced cell death was significantly restored by the ROS scavenger glutathione (GSH), the pharmacological inhibitor of JNK SP600125, or specific JNK knockdown by shRNA. Additionally, signal transducer and activator of transcription 3 (STAT3) activation was suppressed by RA in human osteosarcoma, and this suppression was restored by GSH, SP600125, and JNK‐shRNA. Further investigation showed that STAT3 phosphorylation was increased after JNK knockdown. In a tibial xenograft tumor model, RA induced osteosarcoma apoptosis and notably inhibited tumor growth. Taken together, our results show that RA suppresses proliferation and induces apoptosis by modulating the JNK/c‐Jun and STAT3 signaling pathways in human osteosarcoma. Therefore, RA may be a promising candidate antitumor drug for osteosarcoma intervention.