【摘要】 目的探讨UPR信号通路中重要小分子的抑制剂EerI和4μ8C在宫颈癌中的作用。方法用免疫组化法检测GRP78/BiP、P97、Ubiquitin和IRE1α在正常宫颈鳞状上皮组织及不同临床分期宫颈癌组织中的表达;不同浓度的小分子抑制剂EerI和4μ8C处理宫颈癌HeLa细胞,MTS法检测细胞增殖,流式细胞仪检测细胞凋亡;抗癌药物硼替佐米(BTZ)和顺铂(CDDP)分别联合抑制剂4μ8C和EerI处理HeLa细胞,MTS法检测细胞的增殖。结果 GRP78/BiP、P97、Ubiquitin和IRE1α在不同分期宫颈癌癌巢部位的表达水平较正常宫颈鳞状上皮细胞有显著升高(P<0.05),且随临床分期的不同其表达也存在一定差异;抑制剂EerI和4μ8C呈剂量依赖的方式抑制HeLa细胞生长,促进其凋亡(P<0.05);与单独用药处理相比,抑制剂EerI和4μ8C分别与BTZ和CDDP的联合作用均可显著提高HeLa细胞对两种抗癌药物的敏感性(P<0.05)。结论 UPR通路小分子抑制剂与抗癌药物BTZ和CDDP联用具有协同抗癌活性,这为抗癌新药研发和逆转肿瘤耐药性提供了新的思路。更多还原

【Abstract】 Objective To investigate the therapeutic potential Eeyarestatin-Ⅰ( EerI) and 4μ8C,the small-molecule inhibitors of UPR signaling pathway in the cervical cancer. Methods The protein expression of GRP78 / BiP, P97,Ubiquitin and IRE1α in normal cervical epithelia and cervical cancer were examined by immunohistochemistry. The effect of EerI and 4μ8C on HeLa cell proliferation and apoptosis were measured by MTS assay and flow cytometry,respectively. The combined antiproliferative effects of small-molecule inhibitors were carried out in combination of Bortezomib( BTZ) and Cisplatin( CDDP),respectively. Results GRP78 / BiP,P97,Ubiquitin and IRE1α were significantly up-regulated in cervical cancer compared with normal cervical epithelia and displayed variability in the cervical cancer of different clinical stages( P < 0. 05). EerI and 4μ8C inhibited HeLa cell proliferation in a dose-dependent manner and induced HeLa cell apoptosis in a similar fashion( P < 0. 05). MTS assays in-dicated that combination treatment significantly enhanced the antiproliferative effect of single chemotherapy drugs( P <0. 05). Conclusions Small-molecule inhibitors targeting at the key players of UPR show synergistic effects with other anticancer drugs suggesting a new therapeutic strategy towards cervical cancer.更多还原