Gefitinib resistance in HCC mahlavu cells: Upregulation of CD133 expression, activation of IGF-1R signaling pathway, and enhancement of IGF-1R nuclear translocation
Gefitinib resistance in HCC mahlavu cells: Upregulation of CD133 expression, activation of IGF-1R signaling pathway, and enhancement of IGF-1R nuclear translocation
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DOI：
10.1002/jcp.23041
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发表时间：
2012-07-01
影响因子：
5.6
通讯作者：
Doria, Cataldo
中科院分区：
文献类型：
--
作者：
Bodzin, Adam S.;Wei, Zhengyu;Doria, Cataldo
肝细胞癌（HCC）是原发性肝癌的主要形式，每年在全世界造成50多万人死亡。虽然HCC的发病率仍在上升，但治疗的选择有限，总体生存率很低。获得癌症耐药性仍然是成功治疗的关键障碍之一。显然，需要彻底了解潜在的机制，以设计新的治疗方法和/或改进现有的治疗方法。在本研究中，我们检测了在吉非替尼（一种抑制表皮生长因子受体（EGFR）途径的抗癌药物）治疗下，肝癌Mahlavu细胞中癌症干细胞（CSC）标志物CD133的表达、胰岛素样生长因子1受体（IGF-1R）信号的激活以及IGF-1R的核易位。我们的研究结果表明，Mahlavu细胞表现出较强的吉非替尼耐药性，CD133表达水平在药物治疗后显著增加（从3.88%增加到32%）。此外，吉非替尼处理的细胞显示IGF-1R和Akt磷酸化水平升高，表明该癌症相关信号通路的激活增强。此外，我们通过共聚焦显微镜发现，在吉非替尼处理的细胞中，IGF-1R发生了核易位。在吉非替尼治疗下，IGF-1R核易位增强，并呈剂量依赖性。我们的研究结果表明，吉非替尼治疗后IGF-1R核易位增加可能有助于耐药和IGF1-R激活，这也可能与CD133表达上调有关。j .细胞。物理学报，27(2):2947 - 2952,2012。(C) 2011 Wiley期刊公司
Hepatocellular carcinoma (HCC) is the major form of primary liver cancer which accounts for more than half million deaths annually worldwide. While the incidence of HCC is still on the rise, options of treatment are limited and the overall survival rate is poor. The acquisition of cancer drug resistance remains one of the key hurdles to successful treatment. Clearly, a thorough understanding of the underlying mechanisms is needed for new strategies to design novel treatments and/or to improve the current therapies. In the present study, we examined the expression of cancer stem cell (CSC) marker CD133, the activation of insulin-like growth factor 1 receptor (IGF-1R) signaling, and the nuclear translocation of IGF-1R in HCC Mahlavu cells under the treatment of gefitinib, a cancer drug that inhibits epidermal growth factor receptor (EGFR) pathway. Our results demonstrated that Mahlavu cells exhibited strong gefitinib resistance and the CD133 expression level was dramatically increased (from 3.88% to 32%) after drug treatment. In addition, the gefitinib treated cells displayed increased levels of phosphorylation in IGF-1R and Akt, indicating the intensified activation of this cancer-associated signaling pathway. Moreover, we revealed that IGF-1R underwent nuclear translocation in gefitinib treated cells using confocal microscopy. The IGF-1R nuclear translocation was enhanced under gefitinib treatment and appeared in a dose-dependent manner. Our findings suggest that increased IGF-1R nuclear translocation after gefitinib treatment may contribute to the drug resistance and IGF1-R activation, which might also associate with the upregulation of CD133 expression. J. Cell. Physiol. 227: 29472952, 2012. (C) 2011 Wiley Periodicals, Inc.