在一种人前列腺上皮细胞系中，过氧化物酶体增殖物激活受体γ（PPARγ）和过氧化物酶体增殖物激活受体δ（PPARδ）均影响舒林酸硫化物介导的p21WAF1/CIP1上调。

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

作者信息

Jarvis Morag C, Gray Tim J B, Palmer Colin N A

机构信息

Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.

出版信息

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

DOI:10.1038/sj.onc.1208983

PMID:16091736

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 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.

摘要

包括舒林酸硫化物在内的非甾体抗炎药（NSAIDs）已知在一系列细胞系中具有癌症化学预防活性。这种活性已被证明涉及细胞周期蛋白依赖性激酶抑制剂p21WAF1/CIP1的上调。还已知NSAIDs可作为过氧化物酶体增殖物激活受体（PPAR）激动剂和拮抗剂。在本研究中，我们表明舒林酸硫化物在永生化前列腺上皮细胞系（PNT1A）中既是PPARγ激动剂又是PPARδ拮抗剂。我们利用小干扰RNA（siRNA）技术表明，在PNT1A细胞中，对舒林酸硫化物处理的生长抑制和p21WAF1/CIP1上调都需要PPARγ。此外，PPARδ的过表达部分挽救了这些细胞的生长抑制，并且还显著抑制了舒林酸硫化物介导的p21WAF1/CIP1上调。这些数据共同确定了PPARγ/PPARδ/p21WAF1/CIP1与NSAIDs的癌症化学预防特性之间的新联系。