Peroxisome proliferator-activated receptor γ and retinoic acid receptor synergistically up-regulate the tumor suppressor PTEN in human promyeloid leukemia cells

Peroxisome proliferator-activated receptor γ (PPARγ) and retinoic acid receptors (RARs) have been a focus in chemotherapy for human cancers. The, tumor suppressor PTEN plays a pivotal role in the growth of human cancer cells. We investigated whether costimulation of PPARγ and RAR could synergistically up-regulate PTEN in human leukemia cells and consequently potentiate the inhibition of growth and cell cycle progression of these cells. We found that overexpression of PTEN with the adenoviral vector Ad/PTEN caused growth arrest at the G¹ phase of the cell cycle of HL-60 cells. HL-60 cells treated with either a PPARγ ligand (ciglitazone) or a RAR ligand (all-trans retinoic acid [ATRA]) up-regulated PTEN in HL-60 cells. The 2 compounds in combination showed synergistic effects on PTEN expression at the protein and messenger RNA levels. Moreover, the combination of ciglitazone and ATRA synergistically reduced cell growth rates and cell cycle arrest at the G₁ phase. Our results suggest that, PPARγ and RAR play an important role in controlling the growth of leukemia cells via the up-regulation of PTEN.