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Activation of PPARα by clofibrate sensitizes pancreatic cancer cells to radiation through the Wnt/β-catenin pathway.
- Source :
-
Oncogene [Oncogene] 2018 Feb 15; Vol. 37 (7), pp. 953-962. Date of Electronic Publication: 2017 Oct 23. - Publication Year :
- 2018
-
Abstract
- 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 α (PPARα) is a member of the PPAR nuclear hormone receptor superfamily, which can be activated by fibrate ligands. The clinical relevance of PPARα and its biological function in pancreatic cancer radiosensitivity have not been previously described. In this study, we examined PPARα expression in tissue samples of pancreatic cancer patients. We found significantly higher expression of PPARα in pancreatic cancer tissues than in tumor-adjacent tissues and that the PPARα expression level is inversely associated with higher overall patient survival rate. We further observed that PPARα 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 PPARα silencing and PPARα 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 β-catenin pathway, is downregulated by clofibrate. Chromatin immunoprecipitation analysis confirmed that clofibrate abrogates the binding of nuclear factor-κB to the PTPRZ1 and Wnt8a promoters, ultimately decreasing Wnt/β-catenin signaling activity, which is associated with radiosensitivity. Overall, we demonstrate that PPARα is overexpressed in pancreatic cancer tissues and clofibrate-mediated PPARα activation sensitizes pancreatic cancer cells to radiation through the Wnt/β-catenin pathway.
- Subjects :
- Animals
Anticholesteremic Agents pharmacology
Apoptosis
Biomarkers, Tumor
Cell Proliferation
Follow-Up Studies
Gene Expression Regulation, Neoplastic drug effects
Humans
Male
Mice
Mice, Nude
PPAR alpha genetics
Pancreatic Neoplasms drug therapy
Pancreatic Neoplasms metabolism
Pancreatic Neoplasms pathology
Prognosis
Radiation, Ionizing
Tumor Cells, Cultured
Wnt Proteins genetics
Xenograft Model Antitumor Assays
beta Catenin genetics
Clofibrate pharmacology
Gene Expression Regulation, Neoplastic radiation effects
PPAR alpha metabolism
Pancreatic Neoplasms radiotherapy
Radiation Tolerance drug effects
Wnt Proteins metabolism
beta Catenin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 37
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 29059162
- Full Text :
- https://doi.org/10.1038/onc.2017.401