Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
J Cell Biochem. 2018 Jul;119(7):5913-5920. doi: 10.1002/jcb.26783. Epub 2018 Apr 10.
5-fluorouracil (5-FU) and oxaliplatin (OxaPt) are the main chemotherapeutics for colorectal cancer (CRC). Chemotherapy response rates for advanced CRC remain low, primarily due to intrinsic or acquired chemoresistance. The importance of Notch and Wnt signaling for carcinogenesis of CRC as well as crosstalk of Notch and Wnt signaling with many oncogenic signaling pathways suggest that Notch and Wnt pathways could be responsible for chemoresistance. In this study, we compared changes in Notch and Wnt signaling after 5-FU and OxaPt treatment in CRC cells HCT116 and its chemoresistant sublines HCT116/FU and HCT116/OXA. The levels of Notch1 receptor intracellular domain NICD1 and non-phosphorylated β-catenin, the reporters of Notch and Wnt signaling, were upregulated in untreated chemoresistant HCT116/FU and HCT116/OXA cells. Our data suggest that Notch inhibitor RO4929097 (RO) and Wnt inhibitor XAV939 (XAV) enhance the survival potential of OxaPt-treated cells. The protein level of Notch target gene HES1 was significantly upregulated in chemoresistant HCT116/FU and HCT116/OXA cells, compared to HCT116. HES1 silencing increased viability of HCT116 and its chemoresistant sublines after 5-FU or OxaPt treatment. The results of HES1 downregulation coincide with RO and XAV effects on cell viability of OxaPt-treated cells.
5-氟尿嘧啶（5-FU）和奥沙利铂（OxaPt）是结直肠癌（CRC）的主要化疗药物。晚期 CRC 的化疗反应率仍然很低，主要是由于内在或获得性化疗耐药。Notch 和 Wnt 信号在 CRC 发生中的重要性以及 Notch 和 Wnt 信号与许多致癌信号通路的交叉对话表明，Notch 和 Wnt 通路可能与化疗耐药有关。在这项研究中，我们比较了 HCT116 及其化疗耐药亚系 HCT116/FU 和 HCT116/OXA 中的 CRC 细胞在 5-FU 和 OxaPt 治疗后 Notch 和 Wnt 信号的变化。 Notch1 受体细胞内结构域 NICD1 和非磷酸化 β-连环蛋白的水平， Notch 和 Wnt 信号的报告者，在未经处理的化疗耐药 HCT116/FU 和 HCT116/OXA 细胞中上调。我们的数据表明，Notch 抑制剂 RO4929097（RO）和 Wnt 抑制剂 XAV939（XAV）增强了 OxaPt 处理的细胞的生存潜力。与 HCT116 相比，Notch 靶基因 HES1 的蛋白水平在化疗耐药的 HCT116/FU 和 HCT116/OXA 细胞中显著上调。 HES1 沉默增加了 5-FU 或 OxaPt 处理后 HCT116 和其化疗耐药亚系的活力。 HES1 下调的结果与 RO 和 XAV 对 OxaPt 处理的细胞活力的影响一致。
