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Received for publication January 14, 2003.
Revised February 6, 2003.
Accepted for publication March 7, 2003.
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 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, cyclin D1 and D2. Clofibrate (50 µM), ciprofibrate (50 µM) and 15d-PG J2 (2.5 µM) inhibited c-myb and cyclin D2 expression, while they did not affect c-myc and cyclin D1 expression. Only troglitazone (5µM) 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.
Key words:
C-MYB, C-MYC, CYCLIN D1, CYCLIN D2, HL-60 CELLS, PPAR ALPHA AND GAMMA LIGANDS
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