Polarized cell migration induces cancer type-specific CD133/integrin/Src/Akt/GSK3β/β-catenin signaling required for maintenance of cancer stem cell properties
Journal
Oncotarget
Journal Volume
6
Journal Issue
35
Pages
38029-38045
Date Issued
2015
Author(s)
Abstract
CD133 is widely used as a surface marker to isolate cancer stem cells (CSCs). Here we show that in CSCs CD133 contributes to β-catenin-mediated transcriptional activation and to the self-renewal capacity of sphere-forming and side-population (SP) cells in cell lines from brain, colon and lung cancers, but not gastric or breast cancers. In chromatin immunoprecipitation assays, β-catenin binding to the proximal promoter regions of ITGA2-4 and ITGA10-11 in brain, colon and lung cancer cell lines could be triggered by CD133, and β-catenin also bound to the proximal promoter regions of ITGB6 and ITGB8 in cell lines from gastric and breast cancers. CD133 thus induces β-catenin binding and transcriptional activation of diverse targets that are cancer type-specific. Cell migration triggered by wounding CD133 + cells cultured on ECM-coated dishes can induce polarity and lipid raft coalescence, enhancing CD133/integrin signaling and asymmetric cell division. In response to directional cues, integrins, Src and the Par complex were enriched in lipid rafts, and the assembly and activation of an integrated CD133-integrin-Par signaling complex was followed by Src/Akt/GSK3β signaling. The subsequent increase and nuclear translocation of β-catenin may be a regulatory switch to increase drug resistance and stemness properties. Collectively, these findings 1) indicate that a polarized cell migration-induced CD133/integrin/Src/Akt/GSK3β/β-catenin axis is required for maintenance of CSC properties, 2) establish a function for CD133 and 3) support the rationale for targeting CD133 in cancer treatment.
SDGs
Other Subjects
beta catenin; CD133 antigen; fibrinogen receptor; glycogen synthase kinase 3beta; integrin; protein kinase B; protein tyrosine kinase; AKT1 protein, human; beta catenin; CD133 antigen; CTNNB1 protein, human; glycogen synthase kinase 3; glycogen synthase kinase 3beta; glycoprotein; GSK3B protein, human; Gsk3b protein, mouse; integrin; leukocyte antigen; peptide; PROM1 protein, human; Prom1 protein, mouse; protein kinase B; protein kinase p60; tumor marker; animal experiment; animal model; Article; cancer stem cell; cell migration; cell renewal; chromatin immunoprecipitation; controlled study; fluorescence activated cell sorting; human; human cell; human tissue; immunohistochemistry; ITGA10 gene; ITGA11 gene; ITGA2 gene; ITGA3 gene; ITGA4 gene; lipid raft; mouse; nonhuman; oncogene; plasmid; promoter region; protein binding; side population cell; signal transduction; transcription initiation; animal; apoptosis; cancer stem cell; cell adhesion; cell motion; cell proliferation; drug screening; enzyme immunoassay; female; lung tumor; metabolism; pathology; SCID mouse; side population cell; tumor cell culture; Western blotting; AC133 Antigen; Animals; Antigens, CD; Apoptosis; beta Catenin; Biomarkers, Tumor; Blotting, Western; Cell Adhesion; Cell Movement; Cell Proliferation; Chromatin Immunoprecipitation; Female; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Glycoproteins; Humans; Immunoenzyme Techniques; Integrins; Lung Neoplasms; Mice; Mice, SCID; Neoplastic Stem Cells; Peptides; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins pp60(c-src); Side-Population Cells; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
Publisher
Impact Journals LLC
Type
journal article