Induction of proliferation by 15-deoxy-Δ12,14-prostaglandin J2 and the precursors in monocytic leukemia U937

Peroxisome proliferator-activated receptor gamma ( PPARgamma) is expressed in several human tumors including gastric, lung, colon, prostate and breast. However, the role of PPARgamma signals in leukemia is still unclear. The aim of this study is to evaluate the ability of 15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ(2)), that is a ligand for PPARgamma, on proliferation of human leukemia cell line U937. 15dPGJ(2) at 5 mumol/l stimulated the proliferation. In contrast, 15dPGJ(2) at concentrations of >10 mumol/l inhibited the proliferation through the induction of apoptosis. PGD(2), PGJ(2) and Delta(12)-PGJ(2) (DeltaPGJ(2)), those are precursors of 15dPGJ(2), had similarly proliferative effects, whereas they showed antiproliferative effects at high concentrations. FACScan analysis revealed that PGD(2) at 5 mumol/l, PGJ(2) at 1 mumol/l, DeltaPGJ(2) at 1 mumol/l and 15dPGJ(2) at 5 mumol/l, all accelerated cell cycle progression. Immunoblotting analysis revealed that PGD(2) at 5 mumol/l and 15dPGJ(2) at 5 mumol/l inhibited the expression of phospho-p38, phospho-MKK3/MKK6 and phospho-ATF-2, and the expression of Cdk inhibitors including p18, p27. In contrast, PGJ(2) at 1 mumol/l and DeltaPGJ(2) at 1 mumol/l did not affect the expression of them. These results suggest that 15dPGJ(2) and PGD(2) may, through inactivation of the p38 MAPK pathway, inhibit the expression of Cdk inhibitors, leading to acceleration of proliferation. Copyright (C) 2004 S. Karger AG, Basel.