Possible involvement of p38 in mechanisms underlying acceleration of proliferation by 15-deoxy-Delta(12,14)-prostaglandin J2 and the precursors in leukemia cell line THP-1.
15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ2), which is a ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), induced apoptosis of several human tumors including gastric, lung, colon, prostate, and breast. However, the role of PPARgamma signals in other types of cancer cells (e.g., leukemia) except solid cancer cells is still unclear. The aim of this study is to evaluate the ability of 15dPGJ2 to modify the proliferation of the human leukemia cell line THP-1. 15dPGJ2 at 5 microM stimulated the proliferation in THP-1 at 24 to 72 h after incubation. In contrast, 15dPGJ2 at concentrations above 10 microM inhibited the proliferation through the induction of apoptosis. PGD2, PGJ2, and Delta12-PGJ2 (DeltaPGJ2), precursors of 15dPGJ2, had similar proliferative effects at lower concentrations, whereas they induced apoptosis at high concentrations. 15dPGJ2 and three precursors failed to induce the differentiation in THP-1 as assessed by using the differentiation marker CD11b. FACScan analysis revealed that PGD2 at 5 microM, PGJ2 at 1 microM, DeltaPGJ2 at 1 microM and 15dPGJ2 at 5 microM all accelerated cell cycle progression in THP-1. Immunoblotting analysis revealed that PGD2 at 5 microM and 15dPGJ2 at 5 microM inhibited the expression of phospho-p38, phospho-MKK3/MKK6, and phospho-ATF-2, and the expression of Cdk inhibitors including p18, p21, and p27 in THP-1. In contrast, PGJ2 at 1 microM and DeltaPGJ2 at 1 microM did not affect their expressions. These results suggest that 15dPGJ2 and PGD2 may, through inactivation of the p38 mitogen-activated protein kinase pathway, inhibit the expression of Cdk inhibitors, leading to acceleration of the THP-1 proliferation.
Azuma
Yasutaka
Y
Department of Pharmacology, Osaka Dental University, Japan. aazuma@cc.osaka-dent.ac.jp
Watanabe
Kyoko
K
Date
Masataka
M
Daito
Michiharu
M
Ohura
Kiyoshi
K
D017209:Apoptosis / Q000187:drug effects; D018845:CD11 Antigens / Q000235:genetics / Q000378:metabolism; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival; D002867:Chromones / Q000008:administration & dosage; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D006827:Hydantoins / Q000008:administration & dosage; D007093:Imidazoles / Q000008:administration & dosage; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000008:administration & dosage; D010616:Phenanthrenes / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage; D013997:Time Factors; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*
C410511:1-keto-1,2,3,4-tetrahydrophenanthrene; C477819:15-deoxyprostaglandin J2; D018845:CD11 Antigens; D039481:CD11b Antigen; D002867:Chromones; D005419:Flavonoids; D006827:Hydantoins; D007093:Imidazoles; D009025:Morpholines; D010616:Phenanthrenes; D011725:Pyridines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C030669:BW 245C; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D015230:Prostaglandin D2; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one