title: Wnt activation is implicated in glioblastoma radioresistance.
abstract: Glioblastoma (GBM) patients have dismal median survival even with the most rigorous treatments currently available. Radiotherapy is the most effective non-surgical therapy for GBM patients; however, patients succumb due to tumor recurrence within a year. To develop a curative therapeutic approach, we need to better understand the underlying molecular mechanism of radiation resistance in GBM. Towards this goal, we developed an in vivo orthotopic GBM model system that mimics the radiation response of human GBM, using both established-GBM cell line and patient-derived freshly dissociated GBM specimen. In-vivo ionizing radiation (IR) treatment prolonged the survival of mice with intracranical tumor derived from U373MG, but failed to prevent tumor recurrence. U373MG and GBM578 cells isolated after in-vivo IR (U373-IR and 578-IR) were more clonogenic and enriched with stem cell-like characteristics, compared with mock-treated control tumor cells. Transcriptomic analyses and quantitative real-time reverse-transcription PCR analyses using these matched GBM cells before and after radiation treatment revealed that Wnt pathways were preferentially activated in post-IR GBM cells. U373-IR cells and 578-IR were enriched with cells positive for both active β-catenin (ABC) and Sox2 population, and this subpopulation was further increased after additional in-vitro radiation treatment, suggesting that radiation resistance of GBM is mediated due, in part, to the activation of stem cell-associated pathways including Wnt. Finally, pharmacological and siRNA inhibition of Wnt pathway significantly decreased the survival and clonogenicity of GBM cells and reduced their ABC(+)/Sox2(+) population. Together, these data suggest that Wnt activation is a molecular mechanism to confer GBM radioresistance and an important therapeutic target.
authors.affiliation: Department of Neurosurgery, Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Yonghyun
authors.initials: Y
authors.lastname: Kim
authors.forename: Kang Ho
authors.initials: KH
authors.lastname: Kim
authors.forename: Jeena
authors.initials: J
authors.lastname: Lee
authors.forename: Young-Ae
authors.initials: YA
authors.lastname: Lee
authors.forename: Misuk
authors.initials: M
authors.lastname: Kim
authors.forename: Se Jeong
authors.initials: SJ
authors.lastname: Lee
authors.forename: Kernyu
authors.initials: K
authors.lastname: Park
authors.forename: Heekyoung
authors.initials: H
authors.lastname: Yang
authors.forename: Juyoun
authors.initials: J
authors.lastname: Jin
authors.forename: Kyeung Min
authors.initials: KM
authors.lastname: Joo
authors.forename: Jeongwu
authors.initials: J
authors.lastname: Lee
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000378:metabolism* / Q000532:radiotherapy; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000532:radiotherapy; D020411:Oligonucleotide Array Sequence Analysis; D011836:Radiation Tolerance; D013234:Stem Cells / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051153:Wnt Proteins; D051176:beta Catenin