Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) including sulindac sulfide are known to exert cancer chemopreventative activity in a range of cell lines. This activity has been shown to involve the upregulation of the cyclin-dependent kinase inhibitor p21WAF1/CIP1. It is also known that NSAIDs can act as peroxisome proliferator-activated receptor (PPAR) agonists and antagonists. In this study, we show that sulindac sulfide acts both as a PPARγ agonist and a PPARδ antagonist in an immortalized prostatic epithelial cell line (PNT1A). We utilized siRNA technology to show that PPARγ is required for both growth inhibition and p21WAF1/CIP1 upregulation in response to sulindac sulfide treatment in PNT1A cells. In addition, the overexpression of PPARδ partially rescued these cells from growth inhibition and also dramatically inhibited sulindac sulfide-mediated p21WAF1/CIP1 upregulation. Together these data identify a novel link between PPARγ/PPARδ/p21WAF1/CIP1 and the cancer chemo-preventative properties of NSAIDs.
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Acknowledgements
We thank Dr Sergio Menendez (Surgery and Molecular Oncology, University of Dundee) for the gift of the p21 antibody. This work was funded by Sanofi-Aventis, the Biotechnology and Biological Sciences Research Council (BBSRC), the Association for International Cancer Research (AICR) project grant 04/516 (MJ) and The Medical Research Council (UK) Career Establishment Award G0000119 (CP).
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Jarvis, M., Gray, T. & Palmer, C. Both PPARγ and PPARδ influence sulindac sulfide-mediated p21WAF1/CIP1 upregulation in a human prostate epithelial cell line. Oncogene 24, 8211–8215 (2005). https://doi.org/10.1038/sj.onc.1208983
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DOI: https://doi.org/10.1038/sj.onc.1208983
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