Both PPARgamma and PPARdelta influence sulindac sulfide-mediated p21WAF1/CIP1 upregulation in a human prostate epithelial cell line

Oncogene. 2005 Dec 8;24(55):8211-5. doi: 10.1038/sj.onc.1208983.


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 PPARgamma agonist and a PPARdelta antagonist in an immortalized prostatic epithelial cell line (PNT1A). We utilized siRNA technology to show that PPARgamma is required for both growth inhibition and p21WAF1/CIP1 upregulation in response to sulindac sulfide treatment in PNT1A cells. In addition, the overexpression of PPARdelta 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 PPARgamma/PPARdelta/p21WAF1/CIP1 and the cancer chemo-preventative properties of NSAIDs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Line
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics*
  • Epithelial Cells / drug effects
  • Epithelial Cells / physiology*
  • Gene Expression Regulation* / drug effects
  • Humans
  • Male
  • PPAR delta / physiology*
  • PPAR gamma / physiology*
  • Prostate / cytology
  • Prostate / physiology
  • Sulindac / analogs & derivatives*
  • Sulindac / pharmacology


  • Antineoplastic Agents
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • PPAR delta
  • PPAR gamma
  • Sulindac
  • sulindac sulfide