Peroxisome proliferator-activated receptor ligands affect growth-related gene expression in human leukemic cells

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors. Three subtypes of PPARs (alpha, beta, and gamma) have been identified in different tissues. PPARalpha and PPARgamma ligands inhibit cell proliferation and induce differentiation in several human cell models. We demonstrated that both PPARalpha (clofibrate and ciprofibrate) and PPARgamma ligands (troglitazone and 15 deoxyprostaglandin J2, 15d-PGJ2) inhibited growth, induced the onset of monocytic-like differentiation, and increased the proportion of G(0)/G(1) cells in the HL-60 leukemic cell line. Moreover, 3 days after the treatment with 2.5 muM 15d-PGJ2, an increase in sub-G(0)/G(1) population occurred, compatible with an induction of programmed cell death. To clarify the mechanisms involved in HL-60 growth inhibition due to the effects of PPAR ligands, we investigated their action on the expression of some genes involved in the control of cell proliferation, differentiation, and cell cycle progression such as c-myc, c-myb, and cyclin D1 and D2. Clofibrate (50 muM), ciprofibrate (50 muM), and 15d-PGJ2 (2.5 muM) inhibited c-myb and cyclin D2 expression, whereas they did not affect c-myc and cyclin D1 expression. Only troglitazone (5 muM) decreased c-myc mRNA and protein levels, besides decreasing c-myb and cyclin D2. The down-regulations of c-myb and cyclin D2 expression represent the first evidence of the inhibitory effect exerted by PPAR ligands on these genes. Moreover, the inhibition of c-myc expression by troglitazone may depend on a PPAR-independent mechanism.