title: E804 induces growth arrest, differentiation and apoptosis of glioblastoma cells by blocking Stat3 signaling.
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.
authors.affiliation: 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.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Zhaoxiao
authors.initials: Z
authors.lastname: Du
authors.affiliation: Jinan Infectious Disease Hospital, Jinan Shizhong District, No. 22029 Jingshi Road, Jinan, 250021, Shandong, People's Republic of China.
authors.forename: Zirong
authors.initials: Z
authors.lastname: Zhuang
authors.affiliation: The Second People's Hospital of Liaocheng, No. 306 JianKang Street, Linqing, 252600, Shandong, People's Republic of China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Shuai
authors.initials: S
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Han
authors.initials: H
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Hairong
authors.initials: H
authors.lastname: Feng
authors.affiliation: 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.
authors.forename: Haoyuan
authors.initials: H
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Liyan
authors.initials: L
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 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. aijunhao@sdu.edu.cn.
authors.forename: Aijun
authors.initials: A
authors.lastname: Hao
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D010091:Oximes; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000077022:Survivin; D013997:Time Factors; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D017304:Annexin A5; C494811:BCL2L1 protein, human; C107489:BIRC5 protein, human; C509867:Indirubin E804; D007211:Indoles; D051034:Inhibitor of Apoptosis Proteins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010091:Oximes; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D000077022:Survivin; D051020:bcl-X Protein; D019938:Cyclin D1
keywords: Apoptosis; Differentiation; E804; Glioblastoma; Stat3