College of Pharmacy, Sunchon National University, Sunchon, Jeonnam, 57922, Korea.
Department of Environmental Engineering, Sunchon National University, Sunchon, Jeonnam, 57922, Korea.
J Nanosci Nanotechnol. 2019 Feb 1;19(2):1166-1171. doi: 10.1166/jnn.2019.15899.
ErbB4/KITENIN signaling plays a role in epidermal growth factor receptor (EGFR)-independent EGF pathways mediating the invasiveness and tumorigenesis of colorectal cancer cells. However, whether alterations in ErbB4/KITENIN signaling play a role in the resistance to anti-EGFR therapy remains unclear. Here, we established cetuximab-resistant DLD1 and HT29 cells, and analyzed changes in ErbB4/KITENIN signaling. c-Jun, a final effector in ErbB4/KITENIN-mediated signaling, was upregulated, whereas KITENIN levels remained constant in both cetuximab-resistant cell lines. The phosphorylation of EGFR and ErbB4 was increased in cetuximab-resistant cells, suggesting that ErbB4/KITENIN signaling contributed to the acquisition of cetuximab resistance in the cells. Silencing of KITENIN and/or ErbB4 increased cetuximab sensitivity in cetuximab-resistant cells. This study is the first to report the activation of ErbB4/KITENIN-mediated signaling in cetuximab-resistant colorectal cancer cells and the potential clinical application of ErbB4/KITENIN-targeting therapy for overcoming anti-EGFR resistance.
ErbB4/KITENIN 信号在表皮生长因子受体 (EGFR) 独立的 EGF 途径中发挥作用，介导结直肠癌细胞的侵袭和致瘤性。然而，ErbB4/KITENIN 信号的改变是否在抗 EGFR 治疗的耐药性中起作用尚不清楚。在这里，我们建立了西妥昔单抗耐药的 DLD1 和 HT29 细胞，并分析了 ErbB4/KITENIN 信号的变化。c-Jun 是 ErbB4/KITENIN 介导的信号的最终效应物，在两种西妥昔单抗耐药细胞系中均上调，而 KITENIN 水平保持不变。西妥昔单抗耐药细胞中 EGFR 和 ErbB4 的磷酸化增加，表明 ErbB4/KITENIN 信号有助于细胞获得西妥昔单抗耐药性。沉默 KITENIN 和/或 ErbB4 增加了西妥昔单抗耐药细胞对西妥昔单抗的敏感性。这项研究首次报道了 ErbB4/KITENIN 介导的信号在西妥昔单抗耐药结直肠癌细胞中的激活，以及 ErbB4/KITENIN 靶向治疗克服抗 EGFR 耐药性的潜在临床应用。
