期刊
NEOPLASIA
卷 12, 期 5, 页码 357-365出版社
NEOPLASIA PRESS
DOI: 10.1593/neo.92112
关键词
-
类别
资金
- American Society of Therapeutic Radiology and Oncology
- National Institutes of Health [R03 CA127050-01]
BACKGROUND: Knowledge of factors and mechanisms contributing to the inherent radioresistance of pancreatic cancer may improve cancer treatment. Irradiation inhibits glycogen synthase kinase 3 beta (GSK3 beta) by phosphorylation at serine 9. In turn, release of cytosolic membrane beta-catenin with subsequent nuclear translocation promotes survival. Both GSK3 beta 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 GSK3 beta/beta-catenin axis. RESULTS: Lithium chloride, RNAi-medicated silencing of GSK3 beta, or the expression of a kinase dead mutant GSK3 beta resulted in radioresistance of Panc1 and BxPC3 pancreatic cancer cells. Conversely, ectopic expression of a constitutively active form of GSK3 beta resulted in radio-sensitization of Panc1 cells. GSK3 beta 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 GSK3 beta and beta-catenin showed that GSK3 beta inhibition resulted in stabilization of beta-catenin. Xenografts of both BxPC3 and Panc1 with targeted silencing of GSK3 beta 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 GSK3 beta 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据