PT  - JOURNAL ARTICLE
AU  - Stefano Laurora
AU  - Stefania Pizzimenti
AU  - Federica Briatore
AU  - Alessandra Fraioli
AU  - Maddalena Maggio
AU  - Patrizia Reffo
AU  - Carlo Ferretti
AU  - Mario Umberto Dianzani
AU  - Giuseppina Barrera
TI  - Peroxisome Proliferator-Activated Receptor Ligands Affect Growth-Related Gene Expression in Human Leukemic Cells
AID  - 10.1124/jpet.103.049098
DP  - 2003 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 932--942
VI  - 305
IP  - 3
4099  - http://jpet.aspetjournals.org/content/305/3/932.short
4100  - http://jpet.aspetjournals.org/content/305/3/932.full
SO  - J Pharmacol Exp Ther2003 Jun 01; 305
AB  - Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors. Three subtypes of PPARs (α, β, and γ) have been identified in different tissues. PPARα and PPARγ ligands inhibit cell proliferation and induce differentiation in several human cell models. We demonstrated that both PPARα (clofibrate and ciprofibrate) and PPARγ ligands (troglitazone and 15 deoxy-prostaglandin J2, 15d-PGJ2) inhibited growth, induced the onset of monocytic-like differentiation, and increased the proportion of G0/G1 cells in the HL-60 leukemic cell line. Moreover, 3 days after the treatment with 2.5 μM 15d-PGJ2, an increase in sub-G0/G1 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 μM), ciprofibrate (50 μM), and 15d-PGJ2 (2.5 μM) inhibited c-myb and cyclin D2 expression, whereas they did not affect c-myc and cyclin D1 expression. Only troglitazone (5 μM) 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. The American Society for Pharmacology and Experimental Therapeutics