15-Deoxy-Δ^12,14-prostaglandin J₂ and Its Precursors Target Phosphoinositide 3-kinase and p38 MAPK to Accelerate Proliferation in the Human T Cell Leukemia Cell Line MOLT-4F

Abstract

15-Deoxy-Δ^12,14-prostaglandin J₂ (15dPGJ₂), which is a ligand for peroxisome proliferator-activated receptor γ (PPARγ), induced apoptosis of several human tumors including gastric, lung, colon, prostate and breast. However, the role of PPARγ signals in other types of cancer cells such as leukemia, except solid cancer cells, is still unclear. The aim of this study was to evaluate the ability of 15dPGJ₂ on the proliferation of the human T cell leukemia cell line MOLT-4F. 15dPGJ₂ at 5 μM stimulated proliferation in MOLT-4F at 1 to 3 days after incubation. In contrast, 15dPGJ₂ at concentrations of above 10 μM inhibited proliferation. PGD₂, PGJ₂ and Δ¹²-PGJ₂ (ΔPGJ₂), which 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 proliferation accelerated by 15dPGJ₂ and its three precursors in MOLT-4F. In contrast, PD98059, an extracellular signal-related kinase 1/2 inhibitor, did not affect proliferation accelerated by 15dPGJ₂ and its three precursors. Immunoblotting analysis revealed that PGD₂ at 5 μM, PGJ₂ at 5 μM, ΔPGJ₂ at 1 μM and 15dPGJ₂ at 5 μM potentiated the expression of cyclin A, without affecting the expression of Cdk inhibitors including p18, p21, and p27 in MOLT-4F. 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 MOLT-4F.