Differential effects of interferon alpha-2b and beta on the signaling pathways in human liver cancer cells
Differential effects of interferon alpha-2b and beta on the signaling pathways in human liver cancer cells
复制标题
DOI：
10.1007/s00535-005-1616-x
复制
发表时间：
2005-07-01
影响因子：
6.3
通讯作者：
Murawaki, Y
中科院分区：
文献类型：
--
作者：
Matsumoto, K;Okano, JI;Murawaki, Y
背景干扰素（IFN）已被报道可降低慢性丙型肝炎患者肝细胞癌（HCC）的发生率，并可降低HCC经有效治疗后的复发率。我们研究了干扰素对人肝癌细胞增殖和信号通路的影响。通过改良的3-（4，5-二甲基噻唑-2-基）-2，5-二苯基四唑溴化物（MTT）测定法检测细胞增殖。Western blot分析信号分子的活性。尽管HCC细胞表达IFN受体，但IFN α-2b或IFN-β对细胞生长没有显著调节。然而，细胞外信号调节激酶（ERK）1/2被激活的治疗与IFN α-2b，和ERK 1/2和AKT被激活的治疗与IFN-β，这意味着一个可能的作用，在抵抗干扰素。与我们的预期相反，丝裂原活化的ERK调节激酶（MEK）或磷脂酰肌醇-3-OH激酶（PI 3 K）的抑制并不能调节HCC细胞的增殖。同时，阻断ERK 1/2和AKT信号通路并不影响IFN α-2b引起的G1/S期细胞周期阻滞。IFN α-2b和IFN β激活ERK 1/2和/或AKT，而不依赖于调节HCC细胞的增殖和细胞周期机制。基于信号转导的肝癌治疗方法需要关注其他可能的信号分子，除了ERK 1/2和AKT，当受到干扰素的挑战时。
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 IFN alpha-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 IFN alpha-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 IFN alpha-2b.Conclusion. IFN alpha-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.