Synergistic effect of 4-hydroxynonenal and PPAR ligands in controlling human leukemic cell growth and differentiation.
Peroxisome proliferator-activated receptors play an important role in the differentiation of different cell lines. In this study we demonstrate that PPAR-alpha ligands (clofibrate and ciprofibrate) and PPAR-gamma ligands (troglitazone and 15d-prostaglandin J2) inhibit growth and induce monocytic differentiation in HL-60 cells, whereas only PPAR-gamma ligands inhibit growth of U937 cells. Differentiation was demonstrated by the analysis of surface antigen expression CD11b and CD14, and by the characteristic morphological changes. PPAR-gamma ligands are more effective than PPAR-alpha ligands in the inhibition of cell growth and in the induction of differentiation. The physiological product of lipid peroxidation, 4-hydroxynonenal (HNE), which alone induces granulocytic-like differentiation of HL-60 cells, potentiates the monocytic differentiation induced by ciprofibrate, troglitazone, and 15d-prostaglandin J2. The same HNE treatment significantly inhibits U937 cell growth and potentiates the inhibition of cell growth in PPAR-gamma ligand-treated cells. However, HNE does not induce a significant number of CD14-positive U937 cells. HNE causes a great increase of PPAR-gamma expression in both HL-60 and U937 cells, whereas it does not modify the PPAR-alpha expression. This observation may account for the high synergistic effect displayed by HNE and PPAR-gamma ligands in the inhibition of cell growth and differentiation induction. These results represent the first evidence of the involvement of a product of lipid peroxidation in the modulation of PPAR ligand activity and suggest a relationship between HNE and PPAR ligand pathways in leukemic cell growth and differentiation.
Pizzimenti
Stefania
S
Dipartimento di Medicina e Oncologia Sperimentale, Universita' degli Studi di Torino, Torino, Italy.
Laurora
Stefano
S
Briatore
Federica
F
Ferretti
Carlo
C
Dianzani
Mario U
MU
Barrera
Giuseppina
G
D000447:Aldehydes / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D002994:Clofibrate / Q000494:pharmacology*; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004357:Drug Synergism; D058607:Fibric Acids; D018922:HL-60 Cells; D006801:Humans; D008024:Ligands; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D000077288:Troglitazone; D020298:U937 Cells
D000447:Aldehydes; D002839:Chromans; D058607:Fibric Acids; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D002995:Clofibric Acid; C037112:9-deoxy-delta-9-prostaglandin D2; C019304:ciprofibrate; D002994:Clofibrate; D000077288:Troglitazone; C027576:4-hydroxy-2-nonenal; D015230:Prostaglandin D2