title: GSK3beta and beta-catenin modulate radiation cytotoxicity in pancreatic cancer.
abstract: BACKGROUND
  Knowledge of factors and mechanisms contributing to the inherent radioresistance of pancreatic cancer may improve cancer treatment. Irradiation inhibits glycogen synthase kinase 3beta (GSK3beta) by phosphorylation at serine 9. In turn, release of cytosolic membrane beta-catenin with subsequent nuclear translocation promotes survival. Both GSK3beta and beta-catenin have been implicated in cancer cell proliferation and resistance to death.
  
  
  METHODS
  We investigated pancreatic cancer cell survival after radiation in vitro and in vivo, with a particular focus on the role of the function of the GSK3beta/beta-catenin axis.
  
  
  RESULTS
  Lithium chloride, RNAi-medicated silencing of GSK3beta, or the expression of a kinase dead mutant GSK3beta resulted in radioresistance of Panc1 and BxPC3 pancreatic cancer cells. Conversely, ectopic expression of a constitutively active form of GSK3beta resulted in radiosensitization of Panc1 cells. GSK3beta silencing increased radiation-induced beta-catenin target gene expression as measured by studies of AXIN2 and LEF1 transcript levels. Western blot analysis of total and phosphorylated levels of GSK3beta and beta-catenin showed that GSK3beta inhibition resulted in stabilization of beta-catenin. Xenografts of both BxPC3 and Panc1 with targeted silencing of GSK3beta exhibited radioresistance in vivo. Silencing of beta-catenin resulted in radiosensitization, whereas a nondegradable beta-catenin construct induced radioresistance.
  
  
  CONCLUSIONS
  These data support the hypothesis that GSK3beta modulates the cellular response to radiation in a beta-catenin-dependent mechanism. Further understanding of this pathway may enhance the development of clinical trials combining drugs inhibiting beta-catenin activation with radiation and chemotherapy in locally advanced pancreatic cancer.
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Watson
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Spalding
authors.forename: Steven P
authors.initials: SP
authors.lastname: Zielske
authors.forename: Meredith
authors.initials: M
authors.lastname: Morgan
authors.forename: Alex C
authors.initials: AC
authors.lastname: Kim
authors.forename: Guido T
authors.initials: GT
authors.lastname: Bommer
authors.forename: Hagit
authors.initials: H
authors.lastname: Eldar-Finkelman
authors.forename: Thomas
authors.initials: T
authors.lastname: Giordano
authors.forename: Eric R
authors.initials: ER
authors.lastname: Fearon
authors.forename: Gary D
authors.initials: GD
authors.lastname: Hammer
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
authors.forename: Edgar
authors.initials: E
authors.lastname: Ben-Josef
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression / Q000528:radiation effects*; D020869:Gene Expression Profiling; D020868:Gene Silencing; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy; D011836:Radiation Tolerance / Q000235:genetics*; D011878:Radiotherapy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
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