Differential effects of interferon alpha-2b and beta on the signaling pathways in human liver cancer cells.
BACKGROUND
Interferon (IFN) has been reported to reduce the incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C and the recurrence of HCC after effective treatment. We examined the effect of IFNs on the proliferation and the signaling pathways of human HCC cells.


METHODS
Cellular proliferation was examined by a modified 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. Activities of signaling molecules were evaluated by Western blot analysis.


RESULTS
Cellular growth was not significantly modulated by IFNalpha-2b or by IFN-beta, even though the HCC cells expressed the IFN receptors. However, extracellular signal-regulated kinase (ERK)1/2 was activated by treatment with IFNalpha-2b, and both ERK1/2 and AKT were activated by treatment with IFN-beta, implying a possible role in resistance to IFNs. Contrary to our expectations, inhibition of mitogen-activated ERK-regulating kinase (MEK) or phosphatidylinositol-3-OH kinase (PI3K) did not modulate the proliferation of HCC cells. Also, abrogation of the ERK1/2 and AKT signaling pathways did not affect cell-cycle arrest at the G1/S phase caused by IFNalpha-2b.


CONCLUSIONS
IFNalpha-2b and IFN-beta activated ERK1/2 and/or AKT independently of modulating the proliferation of HCC cells and the cell-cycle machinery. A signal transduction-based approach for HCC treatment needs to focus on other possible signaling molecules besides ERK1/2 and AKT when challenged with IFNs.
Matsumoto
Kazuya
K
Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, 683-8504, Japan.
Okano
Jun-ichi
J
Murawaki
Yoshikazu
Y
D001483:Base Sequence; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects*; D008969:Molecular Sequence Data; D011336:Probability; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D016899:Interferon-beta; D020928:Mitogen-Activated Protein Kinases