Cyclooxygenase-1, but not -2, is upregulated in NB4 leukemic cells and human primary promyelocytic blasts during differentiation.
Cyclooxygenase (COX)-1 or -2 and specific prostaglandin (PG) synthases catalyze the formation of various PGs. We investigated the expression and activity of COX-1 and -2 during granulocyte-oriented maturation induced by all-trans-retinoic acid (ATRA) of NB4 cells, originated from a human acute promyelocytic leukemia (APL), and in blasts from APL patients. The expression of COX isoenzymes or prostaglandin synthases was also investigated in circulating granulocytes and human bone marrow. COX-1 was expressed and enzymatically active in NB4 cells and primary blasts. COX-1 mRNA and protein were induced by ATRA. COX-1 protein increased approximately 2-3.5-fold by culture day 3 in NB4 cells and primary blasts, while basal COX-2 expression was very low and unaffected by ATRA. COX-1-dependent PGE(2) biosynthesis increased during differentiation approx. 5-fold. Indomethacin and the selective COX-1 inhibitor SC-560, but not selective COX-2 inhibition, impaired NB4 differentiation, reducing NADPH-oxidase activity, CD11b and CD11c expression. The immunohistochemistry of granulocytes and myeloid precursors in the bone marrow showed a large prevalence of COX-1 as compared to COX-2. In conclusion, COX-1 is induced during ATRA-dependent maturation and appears to contribute to myeloid differentiation both in vitro and ex vivo, and COX-1 activity may potentiate the differentiation of human APL.Leukemia (2004) 18, 1373-1379. doi:10.1038/sj.leu.2403407 Published online 10 June 2004
Rocca
B
B
Department of Internal Medicine, Catholic University School of Medicine, Rome, Italy. b.rocca@tiscali.it
Morosetti
R
R
Habib
A
A
Maggiano
N
N
Zassadowski
F
F
Ciabattoni
G
G
Chomienne
C
C
Papp
B
B
Ranelletti
F O
FO
D001773:Blood Cells; D001854:Bone Marrow Cells; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D006098:Granulocytes / Q000166:cytology; D006801:Humans; D007527:Isoenzymes / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D007938:Leukemia / Q000201:enzymology / Q000473:pathology; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology* / Q000473:pathology*; D008565:Membrane Proteins; D038042:Myelopoiesis / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D014212:Tretinoin; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone