Phenylacetate (PA) is a member of a class of aromatic
fatty acids that has demonstrated antitumor activity in experimental models and in humans. Previous reports have shown that PA and its analogues can act as
ligands for the
peroxisome proliferator-activated receptor (
PPAR) and thereby regulate certain gene expression through peroxisome proliferator response elements. The role of this activity in the antitumor activity of PA has not been determined. To address this question, we have used the human
neuroblastoma cell line LA-N-5, which expresses
PPARgamma and can be induced to differentiate with PA and with classical
PPARgamma ligands. Our results indicated that the
PPARgamma ligands 15-deoxy-
prostaglandin J2 and
GW1929 as well as PA induced LA-N-5 cells to differentiate to a similar phenotype as evidenced by inhibition of cell proliferation, neurite outgrowth, increased
acetylcholinesterase activity, and decreased N-myc gene expression. Furthermore, induction with all of the compounds was accompanied by up-regulation of
mRNA levels of the nuclear
retinoic acid receptor beta (RARbeta) and specific activation of a reporter gene construct (SVbetaRE-CAT) that contains the canonical RA response element located in the RARbeta promoter. All of the assessed functional and molecular effects of PA on LA-N-5 cells, as well as those of the classical
PPARgamma ligands, were inhibited by cotreatment with specific
PPARgamma antagonists (
GW9662 and/or
GW0072). Taken together, these studies have confirmed a role for
PPARgamma in
neuroblastoma cell biology and indicated that the
PPARgamma signaling pathway plays a direct role in the PA-induced differentiation response of this cell type.