A natural propenoic acid derivative activates peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta).

Aims: Previous studies showed that natural prenyloxyphenylpropanoid derivatives have potent biological properties in vivo. Given the structural similarities between these compounds and known peroxisome proliferator-activated receptor (PPAR) agonists, the present study examined the hypothesis that propenoic acid derivatives activate PPARs.

Main Methods: Chimeric reporter assays were performed to identify propenoic acid derivates that could activate PPARs. Quantitative polymerase chain reaction (qPCR) analysis of wild-type and Pparbeta/delta-null mouse primary keratinocytes was performed to determine if a test compound could specifically activate PPARbeta/delta. A human epithelial carcinoma cell line and primary mouse keratinocytes were used to determine the effect of the compound on cell proliferation.

Key Findings: Three of the propenoic acid derivatives activated PPARs, with the greatest efficacy being observed with prenyloxycinnamic acid derivatives 4'-geranyloxyferulic acid (compound 1) for PPARbeta/delta. Compound 1 increased expression of a known PPARbeta/delta target gene through a mechanism that requires PPARbeta/delta. Inhibition of cell proliferation by compound 1 was found in a human epithelial carcinoma cell line.

Significance: Results from these studies demonstrate that compound 1 can activate PPARbeta/delta and inhibit cell proliferation of a human skin cancer cell line, suggesting that the biological effects of 4'-geranyloxyferulic acid may be mediated in part by activating this PPAR isoform.