Open AccessAntitumor activity of Raddeanin A is mediated by Jun amino‐terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma
Author(s) -
Wang Zhuoying,
Shen Jiakang,
Sun Wei,
Zhang Tao,
Zuo Dongqing,
Wang Hongsheng,
Wang Gangyang,
Xu Jing,
Yin Fei,
Mao Min,
Zhou Zifei,
Hua Yingqi,
Cai Zhengdong
Publication year - 2019
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14008
Subject(s) - stat protein , cancer research , gene knockdown , osteosarcoma , apoptosis , activator (genetics) , mapk/erk pathway , kinase , stat3 , biology , signal transduction , chemistry , microbiology and biotechnology , biochemistry , receptor
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 ERK 1/2 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 SP 600125, or specific JNK knockdown by sh RNA . Additionally, signal transducer and activator of transcription 3 ( STAT 3) activation was suppressed by RA in human osteosarcoma, and this suppression was restored by GSH , SP 600125, and JNK ‐sh RNA . Further investigation showed that STAT 3 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 STAT 3 signaling pathways in human osteosarcoma. Therefore, RA may be a promising candidate antitumor drug for osteosarcoma intervention.