Resveratrol induces chemosensitization to 5-fluorouracil through up-regulation of intercellular junctions, Epithelial-to-mesenchymal transition and apoptosis in colorectal cancer
Resveratrol induces chemosensitization to 5-fluorouracil through up-regulation of intercellular junctions, Epithelial-to-mesenchymal transition and apoptosis in colorectal cancer
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DOI：
10.1016/j.bcp.2015.08.105
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发表时间：
2015-11-01
影响因子：
5.8
通讯作者：
Shakibaei, Mehdi
中科院分区：
文献类型：
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作者：
Buhrmann, Constanze;Shayan, Parviz;Shakibaei, Mehdi
5-氟尿嘧啶（5-FU）是一种用于治疗结直肠癌（CRC）的常用化疗药物，其本身的反应率不足；强调这些患者需要新颖和改进的治疗方案。白藜芦醇是一种天然存在的多酚，具有化学增敏潜力和抗癌特性。白藜芦醇对亲本 CRC 细胞系 (HCT116、SW480) 及其相应的同基因 5-FU 耐药衍生克隆 (HCT116R、SW480R) 的影响通过 MTT 测定、电子显微镜和免疫电子显微镜、细胞核细胞间连接形成和细胞凋亡来检查。 通过 3D 藻酸盐微环境中的蛋白质印迹分析，了解因子-kappaB (NF-kappa B) 和 NF-kappa B 调节的基因产物。白藜芦醇可阻断所有四种 CRC 细胞系的增殖，并协同 5-FU 的侵袭抑制作用。有趣的是，白藜芦醇诱导从 5-FU 诱导的微绒毛形成向平面细胞表面的转变，同时上调 HCT116 和 HCT116R 细胞中桥粒、间隙连接和紧密连接 (claudin-2) 以及粘附分子 (E-钙粘蛋白) 的表达。此外，白藜芦醇通过抑制上皮间质转化 (EMT) 因子（波形蛋白和 slug 减少，E-钙粘蛋白增加）、下调 NF-κ B 激活及其向细胞核的易位以及消除 NF-κ B 调节的基因终产物（MMP-9、caspase-3），显着减弱耐药性。此外，这种抑制是通过抑制 I kappa B α 激酶和 I kappa B α 磷酸化和降解来介导的。我们的结果表明，白藜芦醇可以通过化学增敏、上调细胞间连接和下调 NF-κ B 通路抑制 EMT 表型，从而增强 5-FU 对 CRC 细胞的抗肿瘤作用。 (C) 2015 Elsevier Inc. 保留所有权利。
5-Fluorouracil (5-FU), a common chemotherapeutic agent used for the treatment of colorectal cancer (CRC), by itself has inadequate response rates; highlighting the need for novel and improved treatment regimens for these patients. Resveratrol, a naturally-occurring polyphenol, has been linked with chemosensitizing potential and anticancer properties; however, the underlying mechanisms for these effects remain poorly understood.The effect of resveratrol in parental CRC cell lines (HCT116, SW480) and their corresponding isogenic 5-FU-chemoresistant derived clones (HCT116R, SW480R) was examined by MTT assays, intercellular junction formation and apoptosis by electron- and immunoelectron microscopy, nuclear factor-kappaB (NF-kappa B) and NF-kappa B regulated gene products by western blot analysis in a 3D-alginate microenvironment. Resveratrol blocked the proliferation of all four CRC cell lines and synergized the invasion inhibitory effects of 5-FU. Interestingly, resveratrol induced a transition from 5-FU-induced formation of microvilli to a planar cell surface, which was concomitant with up-regulation of desmosomes, gap- and tight junctions (claudin-2) and adhesion molecules (E-cadherin) expression in HCT116 and HCT116R cells. Further, resveratrol significantly attenuated drug resistance through inhibition of epithelial-mesenchymal transition (EMT) factors (decreased vimentin and slug, increased E-cadherin) and down-regulation of NF-kappa B activation and its translocation to the nucleus and abolished NF-kappa B-regulated gene end-products (MMP-9, caspase-3). Moreover, this suppression was mediated through inhibition of I kappa B alpha kinase and I kappa B alpha phosphorylation and degradation. Our results demonstrate that resveratrol can potentiate the anti-tumor effects of 5-FU on CRC cells by chemosensitizing them, inhibiting an EMT phenotype via up-regulation of intercellular junctions and by down-regulation of NF-kappa B pathway. (C) 2015 Elsevier Inc. All rights reserved.