Interferons and retinoids enhance and dexamethasone suppresses urokinase-mediated plasminogen activation in promyelocytic leukemia cells.
All-trans retinoic acid (RA) has been successfully used in the treatment of patients with acute promyelocytic leukemia (APL). It induces differentiation of APL cells and reduces the bleeding tendency in APL patients. It has been proposed that plasminogen activation could affect the fibrinolytic balance in patients with leukemia. In our earlier study we found that treatment of APL cells with RA results in changes in urokinase (uPA) production. As interferons (IFNs) and dexamethasone can be used together with RA in the treatment of patients with APL, we have now studied the effects of RA together with IFNs and dexamethasone on the plasminogen activation cascade of these cells, including measurement of plasmin generation and uPA receptor (uPAR), using enzyme immunoassays, fluorescence-activated cell sorter analysis and RNA extraction with Northern blotting. Our main results were: (1) plasmin was formed on the surface of APL cells; (2) RA stimulated transiently plasmin generation and increased uPAR mRNA level; (3) IFNs alpha and gamma potentiated RA in its effects on uPA and plasmin activities and on uPAR level; (4) dexamethasone suppressed totally the effect of RA on uPA induction and plasminogen activation; and (5) IFNs and dexamethasone alone did not have potent effects on plasminogen activation. These results may assist in the design of therapy for APL patients.
Mustjoki
S
S
Department of Virology, Haartman Institute, University of Helsinki, Finland.
Tapiovaara
H
H
Sirén
V
V
Vaheri
A
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D004789:Enzyme Activation; D004790:Enzyme Induction; D005341:Fibrinolysin / Q000096:biosynthesis / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology / Q000378:metabolism*; D010958:Plasminogen / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000378:metabolism; D010960:Plasminogen Activators / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis / Q000378:metabolism*
D000970:Antineoplastic Agents; D016898:Interferon-alpha; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014212:Tretinoin; D003907:Dexamethasone; D007371:Interferon-gamma; D010958:Plasminogen; D010960:Plasminogen Activators; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator