Attenuation of STAT3 Phosphorylation Promotes Apoptosis and Chemosensitivity in Human Osteosarcoma Induced by Raddeanin A

Wang, Zhuoying; Wang, Chongren; Zuo, Dongqing; Zhang, Tao; Yin, Fei; Zhou, Zifei; Wang, Hongsheng; Xu, Jing; Mao, Min; Wang, Gangyang; Hua, Yingqi; Sun, Wei; Cai, Zhengdong

doi:10.7150/ijbs.30168

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Int J Biol Sci 2019; 15(3):668-679. doi:10.7150/ijbs.30168 This issue Cite

Research Paper

Attenuation of STAT3 Phosphorylation Promotes Apoptosis and Chemosensitivity in Human Osteosarcoma Induced by Raddeanin A

Zhuoying Wang^1,2*, Chongren Wang^1,2*, Dongqing Zuo^1,2*, Tao Zhang², Fei Yin^1,2, Zifei Zhou², Hongsheng Wang², Jing Xu^1,2, Min Mao², Gangyang Wang², Yingqi Hua^1,2✉, Wei Sun^1,2✉, Zhengdong Cai^1,2✉

1. Department of Orthopaedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China;
2. Shanghai Bone Tumor Institution, Shanghai, China
* These authors contributed equally to this work.

Citation:

Wang Z, Wang C, Zuo D, Zhang T, Yin F, Zhou Z, Wang H, Xu J, Mao M, Wang G, Hua Y, Sun W, Cai Z. Attenuation of STAT3 Phosphorylation Promotes Apoptosis and Chemosensitivity in Human Osteosarcoma Induced by Raddeanin A. Int J Biol Sci 2019; 15(3):668-679. doi:10.7150/ijbs.30168. https://www.ijbs.com/v15p0668.htm

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Abstract

Osteosarcoma (OS) is the most common primary bone malignancy in adolescents. One major obstacle for current OS treatment is drug-resistance. Raddeanin A (RA), an oleanane-type triterpenoid saponin, exerts anti-tumor effects in several tumor models, but the effect of RA in human drug-resistant OS remained to be elucidated. In the present study, we investigated the anti-tumor effects of RA in both drug-sensitive and drug-resistant OS cells and its underlying mechanism. RA inhibited cell proliferation and colony formation and induced apoptotic cell death in a dose-dependent manner in both drug-sensitive and drug-resistant cells. Moreover, RA exposure resulted in the inhibition of interleukin-6 (IL-6)-induced JAK2/STAT3 signaling pathway activation and target gene expression in both drug-sensitive and drug-resistant cells. Meanwhile, we observed significantly increased MDR1 and STAT3 expression in drug-resistant OS cells compared with parental cells. STAT3 overexpression promoted chemo-resistance and MDR1 protein expression in both drug-sensitive OS cells and drug-resistant OS cells, while inhibiting STAT3 with siRNA sensitized OS cells to doxorubicin treatment. In addition, RA synergistically increased doxorubicin toxicity by increasing its cellular uptake, ablating efflux and downregulating MDR1 in drug-resistant cells with attenuation of STAT3 Phosphorylation. Finally, RA suppressed in vivo tumor growth and induced apoptosis in nude mouse using drug-resistant OS tibia orthotopic model. Taken together, RA is a promising potential therapeutic for the treatment of doxorubicin resistance in OS.

Keywords: MDR1, Raddeanin A, osteosarcoma, STAT3, drug-resistance

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APA

Wang, Z., Wang, C., Zuo, D., Zhang, T., Yin, F., Zhou, Z., Wang, H., Xu, J., Mao, M., Wang, G., Hua, Y., Sun, W., Cai, Z. (2019). Attenuation of STAT3 Phosphorylation Promotes Apoptosis and Chemosensitivity in Human Osteosarcoma Induced by Raddeanin A. International Journal of Biological Sciences, 15(3), 668-679. https://doi.org/10.7150/ijbs.30168.

ACS

Wang, Z.; Wang, C.; Zuo, D.; Zhang, T.; Yin, F.; Zhou, Z.; Wang, H.; Xu, J.; Mao, M.; Wang, G.; Hua, Y.; Sun, W.; Cai, Z. Attenuation of STAT3 Phosphorylation Promotes Apoptosis and Chemosensitivity in Human Osteosarcoma Induced by Raddeanin A. Int. J. Biol. Sci. 2019, 15 (3), 668-679. DOI: 10.7150/ijbs.30168.

NLM

CSE

Wang Z, Wang C, Zuo D, Zhang T, Yin F, Zhou Z, Wang H, Xu J, Mao M, Wang G, Hua Y, Sun W, Cai Z. 2019. Attenuation of STAT3 Phosphorylation Promotes Apoptosis and Chemosensitivity in Human Osteosarcoma Induced by Raddeanin A. Int J Biol Sci. 15(3):668-679.

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