title: Peroxisome proliferator-activated receptor ligands affect growth-related gene expression in human leukemic cells.
abstract: 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 microM 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 microM), ciprofibrate (50 microM), and 15d-PGJ2 (2.5 microM) inhibited c-myb and cyclin D2 expression, whereas they did not affect c-myc and cyclin D1 expression. Only troglitazone (5 microM) 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.
authors.affiliation: Department of Medicine, University of Turin, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Laurora
authors.forename: Stefania
authors.initials: S
authors.lastname: Pizzimenti
authors.forename: Federica
authors.initials: F
authors.lastname: Briatore
authors.forename: Alessandra
authors.initials: A
authors.lastname: Fraioli
authors.forename: Maddalena
authors.initials: M
authors.lastname: Maggio
authors.forename: Patrizia
authors.initials: P
authors.lastname: Reffo
authors.forename: Carlo
authors.initials: C
authors.lastname: Ferretti
authors.forename: Mario Umberto
authors.initials: MU
authors.lastname: Dianzani
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Barrera
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002839:Chromans / Q000494:pharmacology; D002994:Clofibrate / Q000494:pharmacology; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D058607:Fibric Acids; D015870:Gene Expression / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D008024:Ligands; D009857:Oncogenes; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*; D000077288:Troglitazone
chemical_list: D000970:Antineoplastic Agents; D002839:Chromans; D058607:Fibric Acids; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D002995:Clofibric Acid; C019304:ciprofibrate; D002994:Clofibrate; D000077288:Troglitazone