title: Emodin suppresses maintenance of stemness by augmenting proteosomal degradation of epidermal growth factor receptor/epidermal growth factor receptor variant III in glioma stem cells.
abstract: There is a growing body of evidence that small subpopulations of cells with stem cell-like characteristics within most solid tumors are responsible for the malignancy of aggressive cancer cells and that targeting these cells might be a good therapeutic strategy to reduce the risk of tumor relapse after therapy. Here, we examined the effects of emodin (1,3,8-trihydroxy-6-methylanthraquinone), an active component of the root and rhizome of Rheum palmatum that has several biological activities, including antitumor effects, on primary cultured glioma stem cells (GSCs). Emodin inhibited the self-renewal activity of GSCs in vitro as evidenced by neurosphere formation, limiting dilution, and soft agar clonogenic assays. Emodin inhibited the maintenance of stemness by suppressing the expression of Notch intracellular domain, nonphosphorylated β-catenin, and phosphorylated STAT3 proteins. In addition, treatment with emodin partially induced apoptosis, reduced cell invasiveness, and sensitized GSCs to ionizing radiation. Intriguingly, emodin induced proteosomal degradation of epidermal growth factor receptor (EGFR)/EGFR variant III (EGFRvIII) by interfering with the association of EGFR/EGFRvIII with heat shock protein 90, resulting in the suppression of stemness pathways. Based on these data, we propose that emodin could be considered as a potent therapeutic adjuvant that targets GSCs.
authors.affiliation: 1 Divisions of Radiation Cancer Research, Research Center for Radio-Senescence , Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Jeongyub
authors.initials: J
authors.lastname: Kim
authors.forename: Jong-Seon
authors.initials: JS
authors.lastname: Lee
authors.forename: Jieun
authors.initials: J
authors.lastname: Jung
authors.forename: Inhye
authors.initials: I
authors.lastname: Lim
authors.forename: Ji-Yun
authors.initials: JY
authors.lastname: Lee
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Park
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D000066673:Cell Self Renewal / Q000187:drug effects; D004642:Emodin / Q000494:pharmacology* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005720:Gamma Rays; D005910:Glioma / Q000473:pathology*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D025941:Protein Interaction Mapping; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D059748:Proteolysis / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018841:HSP90 Heat-Shock Proteins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; C410723:epidermal growth factor receptor VIII; C512478:EGFR protein, human; D066246:ErbB Receptors; D046988:Proteasome Endopeptidase Complex; D004642:Emodin