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Differentiation of Human Neuroblastoma by Phenylacetate Is Mediated by Peroxisome Proliferator-activated Receptor ¹

Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia 30322 [S. H., N. S.], and The Kapiolani Health Research Institute and the University of Hawaii, Honolulu, Hawaii 96813 [R. K. W.]

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 PPAR and can be induced to differentiate with PA and with classical PPAR ligands. Our results indicated that the PPAR 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 ß (RARß) and specific activation of a reporter gene construct (SVßRE-CAT) that contains the canonical RA response element located in the RARß promoter. All of the assessed functional and molecular effects of PA on LA-N-5 cells, as well as those of the classical PPAR ligands, were inhibited by cotreatment with specific PPAR antagonists (GW9662 and/or GW0072). Taken together, these studies have confirmed a role for PPAR in neuroblastoma cell biology and indicated that the PPAR signaling pathway plays a direct role in the PA-induced differentiation response of this cell type.

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