Peroxisome proliferator-activated receptor gamma as a novel target in cancer therapy: Binding and activation by an aromatic fatty acid with clinical antitumor activity

Aromatic fatty acids, of which phenylacetate is a prototype, constitute a c lass of low toxicity drugs with demonstrated antitumor activity in experime ntal models and in humans. Using in vitro models, we show here a tight corr elation between tumor growth arrest by phenylacetate and activation of pero xisome proliferator-activated receptor gamma (PPAR gamma), a member of the nuclear receptor superfamily, In support are the following observations: (a ) the efficacy of phenylacetate as a cytostatic agent was correlated with p retreatment levels of PPAR gamma, as documented using established tumor lin es and forced expression models; (b) in responsive tumor cells, PPAR gamma expression was up-regulated within 2-9 h of treatment preceding increases i n p21waf1, a marker of cell cycle arrest; (c) inhibition of mitogen-activat ed protein kinase, a negative regulator of PPAR gamma, enhanced drug activi ty; and (d) phenylacetate interacted directly with the ligand-binding site of PPAR gamma and activated its transcriptional function. The ability to bi nd and activate PPAR gamma was common to biologically active analogues of p henylacetate and corresponded to their potency as antitumor agents (phenyla cetate < phenylbutyrate < p-chloro-phenylacetate < p-iodo-phenylbutyrate), whereas an inactive derivative, phenylacetylglutamine, had no effect on PPA R gamma, These findings point to PPAR gamma as a novel target in cancer the rapy and provide the first identification of ligands that have selective an titumor activity in patients.