title: Notch1 promotes glioma cell migration and invasion by stimulating β-catenin and NF-κB signaling via AKT activation.
abstract: The Notch signaling pathway has been implicated in both developmental processes and tumorigenesis. Aberrant Notch signaling has been repeatedly demonstrated to facilitate the proliferation and survival of glioma cells by regulating downstream effectors or other signaling pathways. In glioblastoma multiforme specimens from 59 patients, Notch1 was highly expressed in tumor tissues compared with normal brain tissues, and this expression was correlated with elevated AKT phosphorylation and Snail expression. Increased nuclear localization of β-catenin and p50 as well as enhanced IKKα/AKT interaction were also observed in glioma tissues. In U87MG cells, the activation of Notch1 by DLL4 stimulation or by the overexpression of Notch intracellular domain (NICD) resulted in AKT activation and thereby promoted β-catenin activity and NF-κB signaling. Inhibition of EGFR partially blocked the β-catenin and NF-κB signaling stimulated by Notch1 activation. Furthermore, NICD overexpression in U87MG cells led to the upregulated expression of several metastasis-associated molecules, which could be abrogated by the knockdown of either β-catenin or p50. In U87MG and U251 cells, DLL4-induced cellular migration and invasion could be inhibited by either β-catenin or a p50 inhibitor. Collectively, these results indicate that Notch activation could stimulate β-catenin and NF-κB signaling through AKT activation in glioma cells. Thus, Notch activation-stimulated β-catenin and NF-κB signaling synergistically promote the migratory and invasive properties of glioma cells.
authors.affiliation: Department of Neurosurgery, Renji Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.forename: Jiannan
authors.initials: J
authors.lastname: Zhang
authors.forename: Qin
authors.initials: Q
authors.lastname: Mao
authors.forename: Shanquan
authors.initials: S
authors.lastname: Li
authors.forename: Wenhao
authors.initials: W
authors.lastname: Xiong
authors.forename: Yongming
authors.initials: Y
authors.lastname: Qiu
authors.forename: Qiuling
authors.initials: Q
authors.lastname: Xie
authors.forename: Jianwei
authors.initials: J
authors.lastname: Ge
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001921:Brain / Q000473:pathology; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement; D000072159:Dynactin Complex; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D000072159:Dynactin Complex; D036341:Intercellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; C497761:NOTCH1 protein, human; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; C496559:CHUK protein, human; D051550:I-kappa B Kinase