Gsk3β and β-catenin modulate radiation cytotoxicity in pancreatic cancer

Richard L. Watson, Aaron C. Spalding, Steven P. Zielske, Meredith Morgan, Alex C. Kim, Guido T. Bommer, Hagit Eldar-Finkelman, Thomas Giordano, Eric R. Fearon, Gary D. Hammer, Theodore S. Lawrence, Edgar Ben-Josef

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Knowledge of factors and mechanisms contributing to the inherent radioresistance of pancreatic cancer may improve cancer treatment. Irradiation inhibits glycogen synthase kinase 3β (GSK3β) by phosphorylation at serine 9. In turn, release of cytosolic membrane β-catenin with subsequent nuclear translocation promotes survival. Both GSK3β and β-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 GSK3β/β-catenin axis. RESULTS: Lithium chloride, RNAi-medicated silencing of GSK3β, or the expression of a kinase dead mutant GSK3β resulted in radioresistance of Panc1 and BxPC3 pancreatic cancer cells. Conversely, ectopic expression of a constitutively active form of GSK3β resulted in radio-sensitization of Panc1 cells. GSK3β silencing increased radiation-induced β-catenin target gene expression as measured by studies of AXIN2 and LEF1 transcript levels. Western blot analysis of total and phosphorylated levels of GSK3β and β-catenin showed that GSK3β inhibition resulted in stabilization of β-catenin. Xenografts of both BxPC3 and Panc1 with targeted silencing of GSK3β exhibited radioresistance in vivo. Silencing of β-catenin resulted in radiosensitization, whereas a nondegradable β-catenin construct induced radioresistance. CONCLUSIONS: These data support the hypothesis that GSK3β modulates the cellular response to radiation in a β-catenin-dependent mechanism. Further understanding of this pathway may enhance the development of clinical trials combining drugs inhibiting β-catenin activation with radiation and chemotherapy in locally advanced pancreatic cancer.

Original languageEnglish
Pages (from-to)357-365
Number of pages9
JournalNeoplasia
Volume12
Issue number5
DOIs
StatePublished - May 2010

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