Feng Meibao, Wu Xuesong, Zhang Jing, Chen Pei, Qian Senmi, Chang Chengdong
Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University Hangzhou, Zhejiang, P. R. China.
Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University Hangzhou, Zhejiang, P. R. China.
Am J Cancer Res. 2024 May 15;14(5):2088-2102. doi: 10.62347/MEYW3975. eCollection 2024.
Cisplatin is a widely used anti-cancer drug. Unfortunately, many cancers often develop resistance, which contributes to tumor recurrence and poorly prognosis. Growing knowledge has suggested the therapeutic potential of ferroptosis in cancer. Lipocalin2 (LCN2) is demonstrated to be a critical iron metabolic factor and implies in ferroptosis. Here, we aim to explore its role in chemotherapy resistance. The influence of LCN2 on colorectal cancer (CRC) cell chemoresistance and ferroptosis were evaluated by in vitro and in vivo approaches. The interaction between LCN2, NF-ĸB and ferroportin (FPN) was assessed by western blots, immunohistochemistry and dual luciferase reporter assays. Results showed that LCN2 was highly expressed in tumor regression grade 1 (TRG1) cases than that in TRG3 specimens. Loss of LCN2 contributed to resistance to cisplatin-induced ferroptosis. Mechanistically, loss of LCN2 inhibited cisplatin sensitivity and cisplatin-induced ferroptosis through elevating FPN expression which was regulated by NF-ĸB, subsequently reducing Fe mediated Fenton reaction. Furthermore, FPN expression rate was much lower in TRG1 cases, and negative correlation between LCN2 and FPN expression was observed in clinical specimens. Collectively, low LCN2 expression enhances insensitivity of cisplatin to CRC cells via Fenton reaction mediated ferroptosis. LCN2/NF-ĸB/FPN pathway might be potentially utilized for chemoresistance strategy. LCN2 and FPN expression might be a promising biomarker of chemotherapy effect for CRC patients.
顺铂是一种广泛使用的抗癌药物。不幸的是，许多癌症常常会产生耐药性，这会导致肿瘤复发且预后不良。越来越多的知识表明铁死亡在癌症治疗中具有潜在作用。脂质运载蛋白2（LCN2）被证明是一种关键的铁代谢因子，并与铁死亡有关。在此，我们旨在探讨其在化疗耐药中的作用。通过体外和体内实验方法评估LCN2对结直肠癌（CRC）细胞化疗耐药性和铁死亡的影响。通过蛋白质免疫印迹法、免疫组织化学和双荧光素酶报告基因检测评估LCN2、核因子κB（NF-κB）和铁转运蛋白（FPN）之间的相互作用。结果显示，与肿瘤消退分级3（TRG3）标本相比，LCN2在肿瘤消退分级1（TRG1）病例中高表达。LCN2缺失导致对顺铂诱导的铁死亡产生耐药性。机制上，LCN2缺失通过上调由NF-κB调节的FPN表达，进而减少铁介导的芬顿反应，从而抑制顺铂敏感性和顺铂诱导的铁死亡。此外，TRG1病例中的FPN表达率要低得多，并且在临床标本中观察到LCN2与FPN表达呈负相关。总体而言，低LCN2表达通过芬顿反应介导的铁死亡增强了顺铂对CRC细胞的不敏感性。LCN2/NF-κB/FPN通路可能潜在地用于化疗耐药策略。LCN2和FPN表达可能是CRC患者化疗效果的一个有前景的生物标志物。
