Department of Gastroenterology and Metabolism, Nagoya City University, Graduate School of Medical Sciences. 1 Kawasumi, Mizuho, Nagoya 467-8601, Japan.
Anticancer Res. 2011 Oct;31(10):3353-60.
BACKGROUND/AIM: We have reported that embryonic stem cell-expressed Ras (ERas) is expressed in human gastric cancer and is associated with its tumorigenicity. Here, we asked whether ERas plays a role in resistance to chemotherapy in gastric cancer.
To assess the cytotoxicity of chemotherapeutic agents, ERas-overexpressing human gastric cancer GCIY cells were exposed to anticancer agents, including CPT-11 and inhibitor of mammalian target of rapamycin (mTOR). We also investigated the mechanisms by which ERas induces chemoresistance.
ERas-overexpressing clones were significantly more resistant to CPT-11 than were the control (p<0.001). Administration of rapamycin was significantly cytotoxic to the ERas-overexpressing clones compared with the control (p<0.01). Electrophoresis mobility shift assay revealed that ERas enhanced nuclear factor (NF)-κB activity. PCR array demonstrated that ERas up-regulated several multidrug efflux transporter genes, including ABCG2.
ERas induces chemoresistance to CPT-11 via activation of phosphatidylinositol-3 kinase-protein kinase β mTOR pathway and NF-κB, and consequently results in up-regulation of ABCG2.
背景/目的：我们曾报道过，人胃癌中表达胚胎干细胞 Ras（ERas），且其与肿瘤发生有关。在此，我们探讨 ERas 是否在胃癌化疗耐药中发挥作用。
为评估化疗药物的细胞毒性，将 ERas 过表达的人胃癌 GCIY 细胞暴露于包括伊立替康（CPT-11）和哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂在内的抗癌药物中。我们还研究了 ERas 诱导化疗耐药的机制。
与对照组相比，ERas 过表达克隆对 CPT-11 的耐药性显著增强（p<0.001）。雷帕霉素处理对 ERas 过表达克隆的细胞毒性显著高于对照组（p<0.01）。电泳迁移率变动分析显示，ERas 增强了核因子（NF）-κB 活性。PCR 芯片显示，ERas 上调了包括 ABCG2 在内的几个多药外排转运基因。
ERas 通过激活磷脂酰肌醇-3 激酶-蛋白激酶 B mTOR 通路和 NF-κB 诱导对 CPT-11 的化疗耐药，进而导致 ABCG2 的上调。
