title: Nuclear translocation of β-catenin is essential for glioma cell survival.
abstract: Identification of molecular pathways that are essential for cancer cell survival is vital for understanding the underlying biology, as well as to design effective cancer therapeutics. β-catenin, a multifunctional oncogenic protein, participates in cell development. Its multifaceted functions primarily lie to the subcellular distribution. The present study demonstrated that β-catenin accumulated in the nucleus to a greater extent in high-grade gliomas compared with low-grade gliomas. In addition, nuclear localization correlated with a worse prognosis for patients, as determined by immunohistochemical analysis of 74 glioma samples. Nuclear expression of β-catenin was down-regulated in LN229 and U87 glioma cells by a small molecule inhibitor of β-catenin/TCF4 signaling, demonstrating strongly inhibited β-catenin/TCF4 transcriptional activity and STAT3 luciferase activity, as well as decreased mRNA and protein levels of nuclear β-catenin, TCF4, EGFR, AKT1, AKT2 and STAT3. Furthermore, repressed nuclear translocation of β-catenin resulted in inhibition of proliferation and invasiveness, and also induced apoptosis of glioma cells. Similar results were also observed in vivo; intratumoral injection of such small molecule inhibitor downregulated expression of nuclear β-catenin, TCF4, and components of the EGFR pathway, and also delayed tumor growth in nude mice harboring subcutaneous U87 xenografts. Results from the present study provided evidence that nuclear accumulation of β-catenin participated in malignant progression of gliomas and implicated poor prognosis, highlighting it as a potential therapeutic target for gliomas.
authors.affiliation: Department of Neurosurgery, Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Medical University General Hospital, 152, Anshan Road, Heping, Tianjin, 300052, People's Republic of China.
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Shi
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Qian
authors.forename: Lanquan
authors.initials: L
authors.lastname: Li
authors.forename: Junxia
authors.initials: J
authors.lastname: Zhang
authors.forename: Shanjun
authors.initials: S
authors.lastname: Zhu
authors.forename: Jialin
authors.initials: J
authors.lastname: Zhu
authors.forename: Luyue
authors.initials: L
authors.lastname: Chen
authors.forename: Kailiang
authors.initials: K
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.forename: Shizhu
authors.initials: S
authors.lastname: Yu
authors.forename: Peiyu
authors.initials: P
authors.lastname: Pu
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Kang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D003114:Colony-Forming Units Assay; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016133:Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D014178:Translocation, Genetic / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*
chemical_list: C575430:FH535; D013449:Sulfonamides; D051176:beta Catenin; D008156:Luciferases