title: Bcl-w Enhances Mesenchymal Changes and Invasiveness of Glioblastoma Cells by Inducing Nuclear Accumulation of β-Catenin.
abstract: Bcl-w a pro-survival member of the Bcl-2 protein family, is expressed in a variety of cancer types, including gastric and colorectal adenocarcinomas, as well as glioblastoma multiforme (GBM), the most common and lethal brain tumor type. Previously, we demonstrated that Bcl-w is upregulated in gastric cancer cells, particularly those displaying infiltrative morphology. These reports propose that Bcl-w is strongly associated with aggressive characteristic, such as invasive or mesenchymal phenotype of GBM. However, there is no information from studies of the role of Bcl-w in GBM. In the current study, we showed that Bcl-w is upregulated in human glioblastoma multiforme (WHO grade IV) tissues, compared with normal and glioma (WHO grade III) tissues. Bcl-w promotes the mesenchymal traits of glioblastoma cells by inducing vimentin expression via activation of transcription factors, β-catenin, Twist1 and Snail in glioblastoma U251 cells. Moreover, Bcl-w induces invasiveness by promoting MMP-2 and FAK activation via the PI3K-p-Akt-p-GSK3β-β-catenin pathway. We further confirmed that Bcl-w has the capacity to induce invasiveness in several human cancer cell lines. In particular, Bcl-w-stimulated β-catenin is translocated into the nucleus as a transcription factor and promotes the expression of target genes, such as mesenchymal markers or MMPs, thereby increasing mesenchymal traits and invasiveness. Our findings collectively indicate that Bcl-w functions as a positive regulator of invasiveness by inducing mesenchymal changes and that trigger their aggressiveness of glioblastoma cells.
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.
authors.forename: Woo Sang
authors.initials: WS
authors.lastname: Lee
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Woo
authors.forename: Junhye
authors.initials: J
authors.lastname: Kwon
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Park
authors.forename: Jae-Seon
authors.initials: JS
authors.lastname: Lee
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Han
authors.forename: In Hwa
authors.initials: IH
authors.lastname: Bae
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000378:metabolism; D014746:Vimentin / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C491073:BCL2L2 protein, human; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D014746:Vimentin; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2