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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on March 20, 2003; DOI: 10.1124/jpet.103.049098

0022-3565/03/3053-932-942$20.00
JPET 305:932-942, 2003
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CELLULAR AND MOLECULAR

Peroxisome Proliferator-Activated Receptor Ligands Affect Growth-Related Gene Expression in Human Leukemic Cells

Stefano Laurora, Stefania Pizzimenti, Federica Briatore, Alessandra Fraioli, Maddalena Maggio, Patrizia Reffo, Carlo Ferretti, Mario Umberto Dianzani, and Giuseppina Barrera

Departments of Medicine and Experimental Oncology (S.L., S.P., F.B., A.F., M.M., P.R., M.U.D., G.B.) and Anatomy, Pharmacology, and Forensic Medicine (C.F.), University of Turin, Turin, Italy

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors. Three subtypes of PPARs ({alpha}, {beta}, and {gamma}) have been identified in different tissues. PPAR{alpha} and PPAR{gamma} ligands inhibit cell proliferation and induce differentiation in several human cell models. We demonstrated that both PPAR{alpha} (clofibrate and ciprofibrate) and PPAR{gamma} 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.

Received January 14, 2003; accepted March 7, 2003.

Address correspondence to: Prof. Giuseppina Barrera, Dipartimento di Medicina e Oncologia Sperimentale, Sezione di Patologia Generale, Corso Raffaello, 30; 10125 Torino, Italy. E-mail: giuseppina.barrera{at}unito.it




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