Stronger growth-inhibitory effect of interferon (IFN)-β compared to IFN-α is mediated by IFN signaling pathway in hepatocellular carcinoma cells

Abstract

Interferon (IFN) is a promising drug for prevention and treatment of hepatocellular carcinoma (HCC) in combination with chemotherapeutic agents. We previously reported that the spectra of antiproliferative activity and synergistic effect of IFN-β when combined with anticancer drugs are more potent than those of IFN-α in HCC cells. However, the mechanism of the diverse antitumor effects of the IFNs is not understood yet. We studied the expression of IFN α receptor 2 (IFNAR2), STATs, and IFN-α, IFN-β's growth-inhibitory effect, signal transduction and binding to IFNAR2 on three HCC cell lines and a tumor xenografted mouse model (12 animals/group). From the results, IFN-β showed a significantly stronger growth-inhibitory effect than IFN-α on the HuH7 cell line (expressing low IFNAR2), however it was similarly high on PLC/PRF/5 and weak on HLE. In the nude mouse tumor xenograft model, IFN-β injection significantly suppressed tumor volume relative to vehicle injection, while IFN-α showed weaker growth-inhibition. IFN signal transduction (phosphorylated-STAT1, 3) induced by IFN-β was higher than that by IFN-α in HuH7 and tumor xenografts. Pretreatment of hepatoma cells with anti-IFNAR2 antibody blocked the IFN signaling, more for IFN-α. IFN-α's antiproliferative effect was reduced by the antibody in lower concentrations compared to that of IFN-β. Taken together, the HCC cells that express low IFNAR2 and are resistant to IFN-α were sensitive to the growth-inhibitory effect of IFN-β, which might be mediated by stronger IFN signal transduction and distinct binding to IFNAR compared to IFN-α.