Possible mechanisms underlying acceleration of proliferation by 15-deoxy-Δ^{12, 14}-prostaglandin J₂ and the precursors in human T acute lymphoblastic leukemia cell line CCRF-CEM

Abstract

15-Deoxy-Δ^{12, 14}-prostaglandin J₂ (15dPGJ₂ ), that is a ligand for peroxisome proliferator-activated receptor γ (PPAR γ), induced apoptosis of human several tumors including gastric, lung, colon, prostate and breast. However, the role of PPAR y signals in other types of cancer cells such as leukemia except solid cancer cells is still unclear. The aim of this study is to evaluate the ability of 15dPGJ₂ on the proliferation of human T acute lymphoblastic leukemia cell line CCRF-CEM. 15dPGJ₂ at 5 M stimulated the proliferation in CCRF-CEM at 1 to 3 days after incubation. In contrast, 15dPGJ₂ at concentrations of above 10 M inhibited the proliferation. PGD₂, PGJ₂ and Δ¹²PGJ₂ (ΔPGJ₂), those are precursors of 15dPGJ₂, had similarly proliferative effects, whereas they showed anti-proliferative effects at high concentrations. Both SB203580, a p38 mitogen-activated protein kinase ( MAPK ) inhibitor, and LY294002, a phosphoinositide 3-kinase ( PI3K) inhibitor, prevented 15dPGJ₂ and three precursors-accelerated proliferation in CCRF-CEM. In contrast, PD98059, an extracellular signal-related kinase 1/2 inhibitor, did not affect 15dPGJ₂ and three precursors-accelerated proliferation. Immunoblotting analysis revealed that PGD₂ at 5 μM, PGJ₂ at 5 μM, ΔPGJ₂ at 1μ M and 15dPGJ₂ at 5 μM potentiated the expression of cyclin A, without affecting the expression of Cdk inhibitors including p18, p21, p27 in CCRF-CEM. These results suggest that PGD₂, PGJ₂, ΔPGJ₂ and 15dPGJ₂ may, through the activation of p38 MAPK and/or PI3K, potentiate the expression of cyclin A, leading to acceleration of proliferation in CCRF-CEM.