title: The p38 MAPK pathway mediates the growth inhibitory effects of interferon-alpha in BCR-ABL-expressing cells.
abstract: The mechanisms by which interferon-alpha (IFN-alpha) mediates its anti-leukemic effects in chronic myelogenous leukemia (CML) cells are not known. We determined whether p38 MAPK is activated by IFN-alpha in BCR-ABL-expressing cells and whether its function is required for the generation of growth inhibitory responses. IFN-alpha treatment induced phosphorylation/activation of p38 in the IFN-alpha-sensitive KT-1 cell line, but not in IFN-alpha-resistant K562 cells. Consistent with this, IFN-alpha treatment of KT-1 (but not K562) cells induced activation of the small GTPase Rac1, which functions as an upstream regulator of p38. In addition, IFN-alpha-dependent phosphorylation/activation of p38 was induced by treatment of primary granulocytes isolated from the peripheral blood of patients with CML. To define the functional role of the Rac1/p38 MAPK pathway in IFN-alpha signaling, the effects of pharmacological inhibition of p38 on the induction of IFN-alpha responses were determined. Treatment of KT-1 cells with the p38-specific inhibitors SB203580 and SB202190 reversed the growth inhibitory effects of IFN-alpha. On the other hand, the MEK kinase inhibitor PD098059 had no effects, further demonstrating the specificity of these findings. To directly determine the significance of IFN-alpha-dependent activation of p38 in the induction of the anti-leukemic effects of IFN-alpha, we evaluated the effects of p38 inhibition on leukemic colony formation in bone marrow samples of patients with CML. IFN-alpha inhibited leukemic granulocyte/macrophage colony formation in a dose-dependent manner, whereas concomitant treatment with p38 inhibitors reversed such an inhibition. Thus, the Rac1/p38 MAPK pathway is activated by IFN-alpha in BCR-ABL-expressing cells and appears to play a key role in the generation of the growth inhibitory effects of IFN-alpha in CML cells.
authors.affiliation: Section of Hematology-Oncology, Department of Medicine, University of Illinois and the West Side Veterans Affairs Medical Center, Chicago, Illinois 60607, USA.
authors.forename: I A
authors.initials: IA
authors.lastname: Mayer
authors.forename: A
authors.initials: A
authors.lastname: Verma
authors.forename: I M
authors.initials: IM
authors.lastname: Grumbach
authors.forename: S
authors.initials: S
authors.lastname: Uddin
authors.forename: F
authors.initials: F
authors.lastname: Lekmine
authors.forename: F
authors.initials: F
authors.lastname: Ravandi
authors.forename: B
authors.initials: B
authors.lastname: Majchrzak
authors.forename: S
authors.initials: S
authors.lastname: Fujita
authors.forename: E N
authors.initials: EN
authors.lastname: Fish
authors.forename: L C
authors.initials: LC
authors.lastname: Platanias
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D002455:Cell Division; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D016898:Interferon-alpha / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D020014:K562 Cells; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000730:Androstadienes; D004791:Enzyme Inhibitors; D016044:Fusion Proteins, bcr-abl; D019833:Genistein; D007093:Imidazoles; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D014443:Tyrosine; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C098416:MAP-kinase-activated kinase 3; C093642:SB 203580; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole