Both PPARgamma and PPARdelta influence sulindac sulfide-mediated p21WAF1/CIP1 upregulation in a human prostate epithelial cell line.
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.
Jarvis
Morag C
MC
Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.
Gray
Tim J B
TJ
Palmer
Colin N A
CN
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D047494:PPAR delta / Q000502:physiology*; D047495:PPAR gamma / Q000502:physiology*; D011467:Prostate / Q000166:cytology / Q000502:physiology; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047494:PPAR delta; D047495:PPAR gamma; D013467:Sulindac; C025462:sulindac sulfide