J Korean Endocr Soc.  2009 Mar;24(1):25-32. 10.3803/jkes.2009.24.1.25.

Effects of Peroxisome Proliferator-Activated Receptor (PPAR) Delta on the Growth and Invasion of a Thyroid Cancer Cell Line

• Kim WG
• Choi HJ
• Kim EY
• Kim TY
• Kim WB
• Kim SC
• Shong YK

• KMID: 1468492
• DOI: http://doi.org/10.3803/jkes.2009.24.1.25

Abstract

BACKGROUND: Peroxisome proliferator-activated receptor delta (PPAR-delta) is a ligand-activated nuclear transcription factor that is associated with many diseases, such as diabetes, obesity, metabolic syndrome, and cancer. However, the function of PPAR-delta is controversial in carcinogenesis since its ligands may inhibit or promote the growth of cancer cells. The purpose of this study was to determine the effect of GW501516, the specific agonist of PPAR-delta, in the growth and invasiveness of thyroid cancer cell lines by modulation of the target genes, ANGPTL-4 and MCP-1.
METHODS
Three kinds of human cancer cell lines, FRO (thyroid anaplastic carcinoma), NPA (melanoma), and ARO (colon cancer) were treated with GW501516 in serum-free media. Cell viability was assayed using a colorimetric cell counting kit-8 assay. The changes in the level of expression of PPAR-delta and its target genes, angiopoietin-like protein-4 (ANGPTL-4) and monocyte chemotactic protein-1 (MCP-1), were determined by RT-PCR analysis and invasiveness was assessed by a cell invasion assay kit.
RESULTS
GW501516 inhibited the cell growth of cancer cell lines in a dose-dependent manner and modulated the stimulation of ANGPTL-4, as well as inhibition of MCP-1. These effects were more prominent in NPA and ARO, but less effective in the thyroid cancer cell line, which had higher PPAR-delta and lower ANGPTL-4 mRNA levels. The inhibitory effects of GW501516 on cancer invasiveness had a similar pattern.
CONCLUSION
The activation of PPAR-delta by GW501516 reduced the cell growth and invasiveness of the thyroid cancer cell line. This effect of GW501516 was associated with a stimulatory effect of ANGPTL4 and an inhibitory effect of MCP-1 in cancer cell lines. GW501516 was less effective in the thyroid cancer cell line, which had a low basal ANGPTL-4 mRNA level. The findings of our study serve as an impetus for further studies to elucidate the precise role of ANGPTL-4 and PPAR-delta in carcinogenesis.

Keyword

Angiopoietin-like protein-4; Monocyte chemotactic protein-1; Peroxisome proliferator-activated receptor delta; Thyroid cancer

MeSH Terms

Cell Count
Cell Line
Cell Survival
Chemokine CCL2
Culture Media, Serum-Free
Humans
Ligands
Obesity
Peroxisomes
PPAR delta
RNA, Messenger
Thiazoles
Thyroid Gland
Thyroid Neoplasms
Transcription Factors
Chemokine CCL2
Culture Media, Serum-Free
Ligands
PPAR delta
RNA, Messenger
Thiazoles
Transcription Factors

Figure

• 

  Fig. 1 Expression of the PPAR-δ and its target genes, ANGPTL-4 and MCP-1 in human cancer cell lines. Total RNA was isolated from cancer cell lines, ARO, FRO and NPA. The expression of PPARδ, ANGPTL-4, and MCP-1 gene were determined by RT-PCR analysis. N, NPA; F, FRO; A, ARO

• 

  Fig. 2 Effect of GW501516 on cell viability in human cancer cell lines, NPA, ARO, and FRO. Cells were exposed to the indicated concentrations of GW501516 for 48 hours and cell viability was determined by CCK assay. Data presented are mean ± SD for three independent experiments.

• 

  Fig. 3 Effect of GW501516 on invasiveness of human cancer cell lines. A. NPA. B. ARO. C. FRO cells.

• 

  Fig. 4 Effect of GW501516 on PPAR-δ and its target genes, ANGPTL4 and MCP-1 expression. Cells were exposed to 10 uM GW501516 for 0~48 hr. and the change of PPAR-δ, ANGPTL-4, and MCP-1 expressions were determined by RT-PCR analysis. Expression of GAPDH was used as loading controls. A. NPA. B. ARO. C. FRO cells.

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