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MEK and ERK inhibitors enhance the antiproliferative effect of interferon‐α2b
Author(s) -
Romerio Fabio,
Zella Davide
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0120fje
Subject(s) - mapk/erk pathway , kinase , microbiology and biotechnology , cell growth , cancer research , cyclin dependent kinase , cyclin a , mek inhibitor , cell cycle , chemistry , biology , cell , biochemistry
Interferon (IFN)‐α, 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‐α, 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, p21 Waf1 and p27 Kip1 , and decreased cyclin D and E expression. When IFN‐α 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‐α 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.