YBX1作为治疗靶点以抑制LRP1-β-连环蛋白-RRM1轴并克服胰腺癌中的吉西他滨耐药性

YBX1 as a therapeutic target to suppress the LRP1-β-catenin-RRM1 axis and overcome gemcitabine resistance in pancreatic cancer

CANCER LETTERS

影响因子:10.1

分区:医学1区 Top / 肿瘤学2区

发表日期:2024 Oct 10

作者: Borui Li, Faliang Xing, Jingyi Wang, Xiaohong Wang, Chenjie Zhou, Guixiong Fan, Qifeng Zhuo, Shunrong Ji, Xianjun Yu, Xiaowu Xu, Yi Qin, Zheng Li

DOI: 10.1016/j.canlet.2024.217197

摘要

胰腺导管腺癌（PDAC）具有高度恶性且预后较差，且在常见基因突变中缺乏有效的治疗靶点。作为一线化疗药物的吉西他滨，由于药物耐药，5年生存率不足10%。Y-box结合蛋白1（YBX1）与多药耐药基因激活相关，在PDAC的吉西他滨耐药机制中尚未阐明。在体内和体外，我们验证了YBX1在胰腺癌细胞中具有促进作用，尤其是在吉西他滨耐药方面。YBX1通过结合LRP1启动子区域，显著改变胰腺癌细胞中β-连环蛋白的浓度及其分布，从而诱导LRP1的转录。通过转录因子TCF3，β-连环蛋白结合到关键的吉西他滨耐药基因RRM1的启动子区域，促进RRM1的表达。联合使用YBX1抑制剂SU056与吉西他滨在体内外实验中有效降低了吉西他滨的耐药性。高YBX1表达通过YBX1-LRP1-β-连环蛋白-RRM1轴促进胰腺癌的发病和耐药性。将YBX1抑制剂与吉西他滨联合使用可能为克服化疗过程中常见的吉西他滨耐药提供新的联合化疗策略。

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is highly malignant and has a poor prognosis, without effective therapeutic targets in common gene mutations. Gemcitabine, a first-line chemotherapeutic for PDAC, confers <10 % 5-year survival rate because of drug resistance. Y-box binding protein 1 (YBX1), associated with multidrug-resistance gene activation, remains unelucidated in PDAC gemcitabine resistance. In vivo and in vitro, we verified YBX1's promotional effects, especially gemcitabine resistance, in pancreatic cancer cells. YBX1-induced LRP1 transcription by binding to the LRP1 promoter region significantly altered the concentration and distribution of β-catenin in pancreatic cancer cells. Through TCF3, β-catenin bound to the promoter region of RRM1, a key gene for gemcitabine resistance, that promotes RRM1 expression. Combination therapy with the YBX1 inhibitor SU056 and gemcitabine effectively reduced gemcitabine resistance in in vivo and in vitro experiments. High YBX1 expression promoted pathogenesis and gemcitabine resistance in pancreatic cancer through the YBX1-LRP1-β-catenin-RRM1 axis. Combining YBX1 inhibitors with gemcitabine may provide a new direction for combination chemotherapy to overcome gemcitabine resistance, which frequently occurs during chemotherapy for pancreatic cancer.