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

MC Jarvis, TJB Gray, CNA Palmer - Oncogene, 2005 - nature.com
MC Jarvis, TJB Gray, CNA Palmer
Oncogene, 2005nature.com
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 p21 WAF1/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 …
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 p21 WAF1/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 p21 WAF1/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 p21 WAF1/CIP1 upregulation. Together these data identify a novel link between PPARγ/PPARδ/p21 WAF1/CIP1 and the cancer chemo-preventative properties of NSAIDs.
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