1. Academic Validation
  2. 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

  • Cancer Sci. 2019 May;110(5):1746-1759. doi: 10.1111/cas.14008.
Zhuoying Wang 1 Jiakang Shen 1 2 Wei Sun 1 Tao Zhang 1 Dongqing Zuo 1 Hongsheng Wang 1 Gangyang Wang 1 Jing Xu 1 Fei Yin 1 Min Mao 1 Zifei Zhou 1 Yingqi Hua 1 Zhengdong Cai 1
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Shanghai General Hospital of Nanjing Medical University, Shanghai, China.
Abstract

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.

Keywords

Jun amino-terminal kinase; Raddeanin A; SP600125; osteosarcoma; signal transducer and activator of transcription 3.

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