Peroxisome proliferator‐activated receptor γ ligands stimulate myeloid differentiation and lipogenensis in human leukemia NB4 cells

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) plays a central role in adipocyte and macrophage differentiation. Pioglitazone (Actos, AD4833), an antidiabetic drug, and 15-deoxy-∆ 12,14 -prostaglandin J2 (PGJ2) have recently been identified as synthetic and natural ligands for PPARγ, respectively. In this study, we examined the effects of PPARγ ligands on differentiation and lipogenesis in promyelocytic leukemia NB4 cells, in which PPARγ protein was expressed and ligand-stimulated PPARγ-specific transcription of adipocyte fatty-acid binding protein was confirmed. Treatment with PPARγ ligand (AD4833 or PGJ2) alone markedly suppressed proliferation but did not induce differentiation. The combined treatment of the cells with PPARγ ligand and all-trans retinoic acid (ATRA) synergistically induced myelocytic differentiation, as determined by nitroblue tetrazolium reducing ability and cell morphology. During these processes of differentiation, we observed marked accumulation of lipid droplets in the cytoplasm. The cellular triacylglycerol levels increased 2.7-fold after treatment with the inducers. Simultaneously, BODIPY-fatty acid was incorporated into the cytosol and concentrated in lipid droplets. The biosynthesis of triacylglycerol-containing BODIPY-fatty acids was increased twofold in differentiated cells. These findings clearly demonstrate that treatment with PPARγ ligands not only induced differentiation but also stimulated lipogenesis in NB4 cells, indicating a close association between differentiation and lipogenesis in PPARγ-stimulated human myeloid cells.

Activation of peroxisome proliferator-activated receptor-γ induces apoptosis on acute promyelocytic leukemia cells via downregulation of XIAP

“…The results revealed that CGZ induces apoptosis on fresh APL cells, and there was no cell differentiation or maturation in cell morphology during the entire cultural period using Wright's staining observation. A recent study reported that pioglitazone, another synthetic PPAR-Á ligand, stimulates myeloid differentiation in human leukemia NB4 cells (33). In the present studies no differentiation was found in APL cells, these different findings may be a result of by different PPAR-Á ligands.…”

Group IVA Phospholipase A2 Is Necessary for the Biogenesis of Lipid Droplets

“…This is in keeping with Bozza et al (17), who showed that, although aspirin inhibited fatty acid-induced LD formation, this effect was independent of COX inhibition. We also took into account the possibility that AA generated by cPLA 2 ␣ could act as a ligand for peroxisome proliferator-activated receptor-␥ and mediate lipogenesis and LD formation (58). Again, we found that treatment with the peroxisome proliferator-activated receptor-␥ agonist pioglitazone at 50 M did not induce LD over a 6-h treatment nor did it potentiate the effect of FBS; also the antagonist GW9662 at 10 M had no effect.…”

Biomodulatory therapy induces complete molecular remission in chemorefractory acute myeloid leukemia

“…pioglitazone (PGZ)] suppressed clonogenic growth of AML and their combination with ATRA synergistically induced myeloid cell differentiation. 5,6 We herein report that, in a small cohort of 5 elderly AML patients, a novel biomodulatory therapy with low-dose AZA combined with PGZ, and ATRA (APA) induced complete molecular remissions in primary chemorefractory disease.…”