gw-501516 and Adenoma

Peroxisome proliferator-activated receptors (PPARs) are lipid-sensing nuclear receptors that have been implicated in multiple physiologic processes including cancer. Here, we determine that PPARdelta induces cell proliferation through a novel cyclin E1-dependent mechanism and is up-regulated in many human thyroid tumors. The expression of PPARdelta was induced coordinately with proliferation in primary human thyroid cells by the activation of serum, thyroid-stimulating hormone/cyclic AMP, or epidermal growth factor/mitogen-activated protein kinase mitogenic signaling pathways. Engineered overexpression of PPARdelta increased thyroid cell number, the incorporation of bromodeoxyuridine, and the phosphorylation of retinoblastoma protein by 40% to 45% in just 2 days, one usual cell population doubling. The synthetic PPARdelta agonist GW501516 augmented these PPARdelta proliferation effects in a dose-dependent manner. Overexpression of PPARdelta increased cyclin E1 protein by 9-fold, whereas knockdown of PPARdelta by small inhibitory RNA reduced both cyclin E1 protein and cell proliferation by 2-fold. Induction of proliferation by PPARdelta was abrogated by knockdown of cyclin E1 by small inhibitory RNA in primary thyroid cells and by knockout of cyclin E1 in mouse embryo fibroblasts, confirming a cyclin E1 dependence for this PPARdelta pathway. In addition, the mean expression of native PPARdelta was increased by 2-fold 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 PPARdelta mechanism that induces cell proliferation through cyclin E1 and is regulated by growth factor and lipid signals. The data argue for systematic investigation of PPARdelta antagonists as antineoplastic agents and implicate altered PPARdelta-cyclin E1 signaling in thyroid and other carcinomas.

Topics: Adenoma; Adenoma, Oxyphilic; Carcinoma; Carcinoma, Papillary; Cell Differentiation; Cell Proliferation; Cells, Cultured; Cyclic AMP; Cyclin E; Epithelial Cells; Humans; Immunoblotting; Immunoenzyme Techniques; Oncogene Proteins; Phosphorylation; PPAR delta; Retinoblastoma Protein; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Thiazoles; Thyroid Gland; Thyroid Neoplasms; Thyrotropin; Tissue Array Analysis

Peroxisome proliferator-activated receptor (PPAR) delta is a member of the nuclear hormone receptor superfamily. PPARdelta may ameliorate metabolic diseases such as obesity and diabetes. However, PPARdelta's role in colorectal carcinogenesis remains controversial. Here, we present genetic and pharmacologic evidence demonstrating that deletion of PPARdelta decreases intestinal adenoma growth in Apc(Min/+) mice and inhibits tumor-promoting effects of a PPARdelta agonist GW501516. More importantly, we found that activation of PPARdelta up-regulated VEGF in colon carcinoma cells. VEGF directly promotes colon tumor epithelial cell survival through activation of PI3K-Akt signaling. These results not only highlight concerns about the use of PPARdelta agonists for treatment of metabolic disorders in patients who are at high risk for colorectal cancer, but also support the rationale for developing PPARdelta antagonists for prevention and/or treatment of cancer.

Topics: Adenoma; Animals; Cell Line, Tumor; Cell Survival; Disease Progression; Enzyme Activation; Female; Gene Expression Regulation, Neoplastic; Humans; Intestinal Neoplasms; Intestinal Polyps; Male; Mice; Mice, Knockout; PPAR delta; Proto-Oncogene Proteins c-akt; Thiazoles; Vascular Endothelial Growth Factor A

We treated Apc(min) mice, which are predisposed to intestinal polyposis, with a selective synthetic agonist of peroxisome proliferator-activated receptor-delta (PPAR-delta). Exposure of Apc(min) mice to the PPAR-delta ligand GW501516 resulted in a significant increase in the number and size of intestinal polyps. The most prominent effect was on polyp size; mice treated with the PPAR-delta activator had a fivefold increase in the number of polyps larger than 2 mm. Our results implicate PPAR-delta in the regulation of intestinal adenoma growth.

Topics: Adenoma; Adenomatous Polyposis Coli Protein; Animals; Cell Line, Tumor; Dose-Response Relationship, Drug; Genes, APC; Humans; Intestinal Neoplasms; Intestinal Polyps; Ligands; Mice; Receptors, Cytoplasmic and Nuclear; Thiazoles; Transcription Factors