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E804 induces growth arrest, differentiation and apoptosis of glioblastoma cells by blocking Stat3 signaling

  • Laboratory Investigation
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Abstract

Glioblastoma, the most common type of primary malignant brain tumor, is a devastating disease associated with a median survival of approximately 12 months. Here, we have tested E804, the commercially available indirubin derivatives, against U251 and U87 glioblastoma cells. Treatment with E804 significantly inhibits the growth of human glioblastoma cells lines via induction of differentiation and apoptosis. Differentiation induction is coupled with increased expression of glial fibriliary acidic protein, a marker for mature astrocytes. Apoptosis is associated with activation of Caspase 3 and reduction of Bcl-xL and Mcl-1. Furthermore, we demonstrate that E804 reduces signal transducer and activator of transcription-3 (Stat3) signaling to a remarkable extent, suggesting that inactivation of Stat3, at least in part, mediates the effects of this indirubin derivative. Consistently, reduction of Stat3 activity promotes E804-mediated anti-tumor effects, whereas overexpression of Stat3C mutant recues cell apoptosis induced by E804. Taken together, our results indicate that E804 can effectively suppress tumor cell growth, induce tumor cell differentiation and apoptosis mediated partially by Stat3 signaling pathway, suggesting that E804 could be useful for a potential anti-glioblastoma therapeutic approach.

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Acknowledgments

This work was supported by National Natural Science Foundation of China (No. 81402059); China Postdoctoral Science Foundation(No. 2012M521351); Shandong Natural  Science Foundation (No.ZR2012HQ010); Shandong Postdoctoral Science Foundation(No. 201203049).

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    Authors and Affiliations

    1. Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, Shandong University School of Medicine, 44# Wenhua Xi Road, Jinan, 250012, Shandong, People’s Republic of China

      Yanmin Zhang, Zhaoxiao Du, Fen Wang, Shuai Liu, Han Wang, Hairong Feng, Haoyuan Li, Liyan Wang, Xianghong Zhang & Aijun Hao

    2. Jinan Infectious Disease Hospital, Jinan Shizhong District, No. 22029 Jingshi Road, Jinan, 250021, Shandong, People’s Republic of China

      Zirong Zhuang

    3. The Second People’s Hospital of Liaocheng, No. 306 JianKang Street, Linqing, 252600, Shandong, People’s Republic of China

      Yanjun Wang

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    1. Yanmin Zhang
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    Yanmin Zhang and Zhaoxiao Du these authors contributed equally to this work.

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    Zhang, Y., Du, Z., Zhuang, Z. et al. E804 induces growth arrest, differentiation and apoptosis of glioblastoma cells by blocking Stat3 signaling. J Neurooncol 125, 265–275 (2015). https://doi.org/10.1007/s11060-015-1917-8

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