Rapid inhibition of MAPK signaling and anti-proliferation effect via JAK/STAT signaling by interferon-alpha in hepatocellular carcinoma cell lines.
The potential anti-proliferation effect of interferon-alpha (IFN-alpha) against hepatocellular carcinoma (HCC) and its growth inhibitory mechanisms remain unclear. We examined four human HCC cell lines and every cell line had the anti-proliferative effect of IFN-alpha. The PLC/PRF/5 cell line, which expressed the IFN receptor most abundantly, responded most effectively to IFN-alpha stimulation. Here, we delineate the anti-proliferative effect of IFN-alpha via the MAPK pathway in human HCC cell lines. IFN-alpha retarded G1/S transition with no evidence of apoptosis and inhibited cell proliferation. IFN-alpha diminished the phosphorylation of both extracellular signal-regulated kinase (ERK) and mitogen-activated ERK-regulating kinase (MEK), but not Raf, within 5 min. Knockdown of signal transducers of activation and transcription1 (STAT1) or Janus kinase1 (JAK1) suppressed the reduction of phosphorylation both of ERK and MEK and diminished the growth inhibition by IFN-alpha. These results suggest that IFN-alpha induces anti-proliferative signaling via the JAK/STAT pathway downstream of IFN-alpha receptors and may reduce the growth stimulation signaling by cross-talk with the MEK/ERK pathway without IFN-alpha-induced transcription.
Inamura
Kentaro
K
Department of Molecular Biology and Molecular Oncology, Graduate School of Comprehensive Human Science, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan.
Matsuzaki
Yasushi
Y
Uematsu
Naoya
N
Honda
Akira
A
Tanaka
Naomi
N
Uchida
Kazuhiko
K
D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D016898:Interferon-alpha / Q000494:pharmacology*; D053613:Janus Kinase 1; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism
D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D048049:Extracellular Signal-Regulated MAP Kinases