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Activation of PPARα by clofibrate sensitizes pancreatic cancer cells to radiation through the Wnt/β-catenin pathway

Oncogene volume 37, pages 953–962 (2018)Cite this article

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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.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81522039, 81573080, 81673100 and 31670857), the Key Scientific Development Program of China (2016YFC0904700 and 2016YFC0904702), the Suzhou Key Medical Center (SZZX201506) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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  1. J Xue and W Zhu: J Xue and W Zhu contributed equally to this work.

Authors and Affiliations

  1. School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, China

    J Xue, W Zhu, J Song, Y Jiao, C Yu, J Cao & S Zhang

  2. Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China

    J Xue, W Zhu, J Song, Y Jiao, C Yu, J Cao & S Zhang

  3. Department of Oncology, The Affiliated Hospital of Nanjing Medical University, Changzhou No.2 People’s Hospital, Changzhou, China

    J Luo

  4. Suzhou Cancer Center Core Laboratory, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, China

    J Zhou & J Wu

  5. Zhejiang Key Laboratory of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China

    M Chen & S Zhang

  6. Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA

    W-Q Ding

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Xue, J., Zhu, W., Song, J. et al. Activation of PPARα by clofibrate sensitizes pancreatic cancer cells to radiation through the Wnt/β-catenin pathway. Oncogene 37, 953–962 (2018). https://doi.org/10.1038/onc.2017.401

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