Epigenetic induction of lipocalin 2 expression drives acquired resistance to 5-fluorouracil in colorectal cancer through integrin beta 3/SRC pathway
Epigenetic induction of lipocalin 2 expression drives acquired resistance to 5-fluorouracil in colorectal cancer through integrin beta 3/SRC pathway
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脂质运载蛋白 2 表达的表观遗传诱导通过整合素 β 3/SRC 途径驱动结直肠癌对 5-氟尿嘧啶的获得性耐药
DOI：
10.1038/s41388-021-02029-4
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发表时间：
2021
期刊：
影响因子：
8
通讯作者：
Lu Xincheng
中科院分区：
文献类型：
--
作者：
Zhang Wenyi;Pan Rulu;Lu Mei;Zhang Qian;Lin Ziqi;Qin Yuan;Wang Zhanyu;Gong Siqing;Lin Huan;Chong Shuyi;Lu Liting;Liao Wanqin;Lu Xincheng
5-氟尿嘧啶（5-FU）的治疗效果往往会因耐药性的发展而降低。我们观察到脂质运载蛋白2（LCN 2）的表达在一个新建立的5-FU耐药的结直肠癌（CRC）细胞系显着上调。在这项研究中，我们证明了5-FU处理的CRC细胞通过LCN 2启动子去甲基化引起的LCN 2上调而产生耐药性，并且LCN 2和NF-κB之间的反馈进一步放大了LCN 2的表达。LCN 2高表达与结直肠癌患者预后不良相关。LCN 2通过激活SRC/AKT/ERK介导的抗凋亡程序减弱5-FU的细胞毒性。从机制上讲，LCN 2-整联蛋白β3相互作用增强整联蛋白β3的稳定性，从而将SRC募集到细胞膜上进行自激活，导致下游AKT/ERK级联激活。靶向LCN 2或SRC损害了具有LCN 2诱导的5-FU抗性的CRC细胞的生长。我们的研究结果证明了对5-FU获得性耐药的新机制，表明LCN 2可用作晚期CRC的生物标志物和/或治疗靶点。
The therapeutic efficacy of 5-fluorouracil (5-FU) is often reduced by the development of drug resistance. We observed significant upregulation of lipocalin 2 (LCN2) expression in a newly established 5-FU-resistant colorectal cancer (CRC) cell line. In this study, we demonstrated that 5-FU-treated CRC cells developed resistance through LCN2 upregulation caused by LCN2 promoter demethylation and that feedback between LCN2 and NF-κB further amplified LCN2 expression. High LCN2 expression was associated with poor prognosis in CRC patients. LCN2 attenuated the cytotoxicity of 5-FU by activating the SRC/AKT/ERK-mediated antiapoptotic program. Mechanistically, the LCN2-integrin β3 interaction enhanced integrin β3 stability, thus recruiting SRC to the cytomembrane for autoactivation, leading to downstream AKT/ERK cascade activation. Targeting LCN2 or SRC compromised the growth of CRC cells with LCN2-induced 5-FU resistance. Our findings demonstrate a novel mechanism of acquired resistance to 5-FU, suggesting that LCN2 can be used as a biomarker and/or therapeutic target for advanced CRC.