NDLI: PPARδ INDUCES CELL PROLIFERATION BY A CYCLIN E1-DEPENDENT MECHANISM AND IS UPREGULATED IN THYROID TUMORS

Content Provider	PubMed Central
Author	Zeng, Lingchun Geng, Yan Maria, Tretiakova Yu, Xuemei Sicinski, Peter Kroll, Todd G.
Abstract	Peroxisome proliferator-activated receptors (PPARs) are lipid sensing nuclear receptors that have been implicated in multiple physiologic processes including cancer. Here, we determine that PPARδ induces cell proliferation through a novel cyclin E1-dependent mechanism and is upregulated in many human thyroid tumors. The expression of PPARδ was induced coordinately with proliferation in primary human thyroid cells by activation of serum, TSH/cAMP/pKa or EGF/MEK/ERK mitogenic signaling pathways. Engineered overexpression of PPARδ increased thyroid cell number, the incorporation of BrdU and the phosphorylation of Rb 40–45% in just 2 days, one usual cell population doubling. The synthetic PPARδ agonist GW501516 augmented these PPARδ proliferation effects in a dose-dependent manner. Overexpression of PPARδ increased cyclin E1 protein 9-fold, whereas knock down of PPARδ by siRNA reduced both cyclin E1 protein and cell proliferation 2-fold. Induction of proliferation by PPARδ wasabrogated by knockdown of cyclin E1 by siRNA in primary thyroid cells and by knockout of cyclin E1 in mouse embryo fibroblasts, confirming a cyclin E1 dependence for this PPARδ pathway. In addition, the mean expression of native PPARδ was increased 2- to 5-fold (p<0.0001) and correlated with that of the in situ proliferation marker Ki67 (R=0.8571; p=0.02381) in six different classes of benign and malignant human thyroid tumors. Our experiments identify a PPARδ mechanism that induces cell proliferation through cyclin E1 and is regulated by growth factor and lipid signals. The data argue for systematic investigation of PPARδ antagonists as anti-neoplastic agents and implicate altered PPARδ-cyclin E1 signaling in thyroid and other carcinomas.
Related Links	http://dx.doi.org/10.1158/0008-5472.can-08-0855
Ending Page	6586
Page Count	9
Starting Page	6578
File Format	PDF
ISSN	00085472
e-ISSN	15387445
Journal	Cancer research
Issue Number	16
Volume Number	68
Language	English
Publisher Date	2008-08-15
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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