The p38 MAPK pathway mediates the growth inhibitory effects of interferon-alpha in BCR-ABL-expressing cells

• Published in: The Journal of biological chemistry Vol. 276; no. 30; pp. 28570 - 28577
• Main Authors: Mayer, I A, Verma, A, Grumbach, I M, Uddin, S, Lekmine, F, Ravandi, F, Majchrzak, B, Fujita, S, Fish, E N, Platanias, L C
• Format: Journal Article
• Language: English
• Published: United States 27.07.2001
• Subjects: Abl gene; Androstadienes - pharmacology; BCR gene; Cell Division; Cell Line; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Enzyme Activation; Enzyme Inhibitors - pharmacology; Fusion Proteins, bcr-abl - metabolism; Genistein - pharmacology; Humans; Imidazoles - pharmacology; Immunoblotting; Interferon-alpha - metabolism; Intracellular Signaling Peptides and Proteins; K562 Cells; MAP Kinase Signaling System; mitogen-activated protein kinase; Mitogen-Activated Protein Kinases - metabolism; p38 Mitogen-Activated Protein Kinases; p38 protein; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Pyridines - pharmacology; Tyrosine - metabolism; Wortmannin
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M011685200

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.