MEK and ERK inhibitors enhance the anti-proliferative effect of interferon-alpha2b.
Interferon (IFN)-alpha, initially characterized as an antiviral cytokine, affects several cellular functions. It is used in clinical practice for the treatment of several tumors, including hematopoietic malignancies, due to its antiproliferative effects. To better characterize the molecular mechanism(s) underlying this property, we conducted our studies in purified primary CD4+ T cells stimulated with anti-CD3 and interleukin (IL)-2. Upon treatment with IFN-alpha, the cells were blocked in the G0/G1 phase of the cell cycle and exhibited impaired entry into S phase and reduced proliferation. Moreover, we detected short- and long-term inhibition of extracellular signal-regulated kinase (ERK) and mitogen-activated ERK-regulating kinase (MEK) function, known to control cellular proliferation. The activity of the upstream regulators, Ras and Raf-1, was not affected. Analysis of downstream events controlled by the MEK/ERK pathway showed reduced activity of cyclin-dependent kinase (Cdk)-2 and -4, high levels of the mitotic inhibitors, p21Waf1 and p27Kipl, and decreased cyclin D and E expression. When IFN-alpha was used in combination with MEK and ERK inhibitors, we observed a dose-dependent additive effect in reducing cellular proliferation. Our data demonstrate that IFN-alpha may be associated with other molecules to inhibit cellular growth by targeting the MEK/ERK pathway. This may eventually lead to new clinical strategies to strengthen its anticancer effect.
Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, Maryland 2120, USA.
Fabio
F
Romerio
Davide
D
Zella
D000873:Anthracenes; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D018631:ras Proteins / Q000378:metabolism
D000873:Anthracenes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D010569:Perylene; C004965:hypericin; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one