title: Tetrandrine inhibits glioma stem-like cells by repressing β-catenin expression.
abstract: Cancer stem cells (CSCs) in glioma are often responsible for relapse and resistance to therapy. The purpose of the present study was to confirm the self-renewal and migration inhibitory effects of tetrandrine (Tet), which is a compound extracted from the dried root of Stephania tetrandra S. Moore, toward glioma stem-like cells (GSLCs) and to examine the associated molecular mechanisms. Using a neurosphere culture technique, we enriched the GSLC population from the human glioblastoma cell lines U87 and U251. Cells were analyzed using cell counting kit-8 (CCK-8), western blotting, flow cytometry, transwell assay and immunofluorescence staining. GSLCs displayed properties of neural stem cells, including elevated expression of the cancer stem cell marker ALDH1 and β-catenin. We found that Tet treatment decreased sphere formation in GSLCs in a dose-dependent manner using tumor spheroid formation assay. The GSK3β inhibitor BIO maintained sphere formation and migration capacity in GSLCs, whereas the β-catenin/TCF transcription inhibitor ICG-001 decreased sphere formation and the migration capacity of GSLCs. The proportion of apoptotic GSLCs also increased in response to ICG-001 treatment. These results indicate that β-catenin activity is vital in maintaining neural stem cell traits of GSLCs. Tet inhibits cell viability, neurosphere formation and migration of GSLCs in vitro. Importantly, Tet treatment significantly repressed the nuclear translocation and expression of β-catenin and induced apoptosis in GSLCs, as indicated in part by the upregulation of Bax, the cleavage of PARP and the downregulation of Bcl-2. The present study demonstrates that the inhibition of β-catenin in CSCs by Tet could be an effective strategy for the treatment of glioma.
authors.affiliation: Department of Pathology, Medical School of Jinan University, Guangzhou, Guangdong 510632, P.R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Medical School of Jinan University, Guangzhou, Guangdong 510632, P.R. China.
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Wen
authors.affiliation: Department of Pathology, Medical School of Jinan University, Guangzhou, Guangdong 510632, P.R. China.
authors.forename: Ji-Wei
authors.initials: JW
authors.lastname: Ma
authors.affiliation: Department of Pathology, Medical School of Jinan University, Guangzhou, Guangdong 510632, P.R. China.
authors.forename: Jie-Cheng
authors.initials: JC
authors.lastname: Ye
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathology, Medical School of Jinan University, Guangzhou, Guangdong 510632, P.R. China.
authors.forename: Jian-Xian
authors.initials: JX
authors.lastname: Huang
authors.affiliation: Department of Pathology, Medical School of Jinan University, Guangzhou, Guangdong 510632, P.R. China.
authors.forename: Chao-Yue
authors.initials: CY
authors.lastname: Meng
authors.affiliation: Department of Pathology, Medical School of Jinan University, Guangzhou, Guangdong 510632, P.R. China.
authors.forename: Xiao-Ze
authors.initials: XZ
authors.lastname: Xu
authors.affiliation: School of Medicine, Shenzhen University, Shenzhen, Guangdong 518060, P.R. China.
authors.forename: Shao-Xiang
authors.initials: SX
authors.lastname: Wang
authors.affiliation: Department of Pathology, Medical School of Jinan University, Guangzhou, Guangdong 510632, P.R. China.
authors.forename: Xue-Yun
authors.initials: XY
authors.lastname: Zhong
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D044182:Benzylisoquinolines / Q000008:administration & dosage*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D011744:Pyrimidinones / Q000008:administration & dosage; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D044182:Benzylisoquinolines; D019086:Bridged Bicyclo Compounds, Heterocyclic; C492448:ICG 001; D011744:Pyrimidinones; D051028:bcl-2-Associated X Protein; D051176:beta Catenin; C009438:tetrandrine