Phosphatidic acid induces the differentiation of human acute promyelocytic leukemic cells into dendritic cell-like.
We investigated whether phosphatidic acid (PA) can differentiate the promyelocytic leukemia (PML)-retinoic acid receptor alpha (RAR alpha)-expressing acute promyelocytic leukemic cell line, NB4, to dendritic cell (DC)-like cells. Dioctanoyl-PA alone upregulated the expression of DC markers. The expression of DC markers on NB4 cells was potentiated by the overexpression of phospholipase D and upregulation was blocked by the addition of n-butanol, an inhibitor of PA production. The expression of CD11c, CD83, and CCR7 in PA-treated NB4 cells was further increased by tumor necrosis factor (TNF)-alpha treatment. Increased functional capacities were also found in PA-differentiated and TNF-alpha-activated NB4 cells with respect to changes in T-cell proliferation, cytokine production, endocytic activity, and cytolytic capacity against undifferentiated NB4 cells. PA alone increased the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2. The expression of DC markers was downregulated by PD98059, a specific inhibitor of ERK kinase or transient transfection of mutant-ERK. The level of PML-RAR alpha fusion protein was decreased by PA treatment and PD98059 blocked the decrease of PML-RAR alpha. These results suggest that PA induces differentiation of NB4 cells into DC-like cells and that the upregulation of antigen presenting cell markers is mediated by the activation of ERK and the downregulation of PML-RAR alpha levels.
Jin
Jun-O
JO
Medical Research Center for Cancer Molecular Therapy, Dong-A University, Busan 602-714, Korea.
Park
Hae-Young
HY
Kim
Ja-Woong
JW
Park
Joo-In
JI
Hong
Young-Seoub
YS
Min
Do Sik
do S
Kwak
Jong-Young
JY
D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000276:immunology / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010587:Phagocytosis; D010712:Phosphatidic Acids / Q000494:pharmacology / Q000502:physiology*; D010739:Phospholipase D / Q000378:metabolism; D010766:Phosphorylation; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
D015415:Biomarkers; D016207:Cytokines; D005419:Flavonoids; D015514:Oncogene Proteins, Fusion; D010712:Phosphatidic Acids; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C084527:dioctanoylphosphatidic acid; D048049:Extracellular Signal-Regulated MAP Kinases; D010739:Phospholipase D; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one