科研之友
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摘要
Radiotherapy is emerging as an important modality for the local control of pancreatic cancer, but pancreatic cancer cell radioresistance remains a serious concern. Peroxisome proliferator-activated receptor a (PPAR alpha) is a member of the PPAR nuclear hormone receptor superfamily, which can be activated by fibrate ligands. The clinical relevance of PPAR alpha and its biological function in pancreatic cancer radiosensitivity have not been previously described. In this study, we examined PPAR alpha expression in tissue samples of pancreatic cancer patients. We found significantly higher expression of PPAR alpha in pancreatic cancer tissues than in tumor-adjacent tissues and that the PPAR alpha expression level is inversely associated with higher overall patient survival rate. We further observed that PPAR alpha activation by its agonist clofibrate sensitizes pancreatic cancer cells to radiation by modulating cell cycle progression and apoptosis in several pancreatic cancer cell lines. Small interfering RNA-mediated PPAR alpha silencing and PPAR alpha blockade by the antagonist GW6471 abolish the effect of clofibrate on radiosensitization. An in vivo study showed that PANC1 xenografts treated with clofibrate are more sensitive to radiation than untreated xenografts. mRNA profiling by microarray analysis revealed that the expression of PTPRZ1 and Wnt8a, two core components of the beta-catenin pathway, is downregulated by clofibrate. Chromatin immunoprecipitation analysis confirmed that clofibrate abrogates the binding of nuclear factor-kappa B to the PTPRZ1 and Wnt8a promoters, ultimately decreasing Wnt/beta-catenin signaling activity, which is associated with radiosensitivity. Overall, we demonstrate that PPARa is overexpressed in pancreatic cancer tissues and clofibrate-mediated PPARa activation sensitizes pancreatic cancer cells to radiation through the Wnt/beta-catenin pathway.
