RT Journal Article
SR Electronic
T1 Peroxisome Proliferator-Activated Receptor Ligands Affect Growth-Related Gene Expression in Human Leukemic Cells
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 932
OP 942
DO 10.1124/jpet.103.049098
VO 305
IS 3
A1 Stefano Laurora
A1 Stefania Pizzimenti
A1 Federica Briatore
A1 Alessandra Fraioli
A1 Maddalena Maggio
A1 Patrizia Reffo
A1 Carlo Ferretti
A1 Mario Umberto Dianzani
A1 Giuseppina Barrera
YR 2003
UL http://jpet.aspetjournals.org/content/305/3/932.abstract
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