The Interaction of Calcium-Sensing Receptor with KIF11 Enhances Cisplatin Resistance in Lung Adenocarcinoma via BRCA1/cyclin B1 pathway.

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
International Journal of Biological Sciences Pub Date : 2024-07-15 eCollection Date: 2024-01-01 DOI:10.7150/ijbs.92046
Fuhao Wang, Xing Fu, Ming Chang, Tianzi Wei, Risheng Lin, Haibo Tong, Xiao Zhang, Runzhu Yuan, Zhiqing Zhou, Xin Huang, Wei Zhang, Wenmei Su, Yi Lu, Zhen Liang, Jian Zhang
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引用次数: 0

Abstract

Cisplatin (DDP) is commonly used in the treatment of non-small cell lung cancer (NSCLC), including lung adenocarcinoma (LUAD), and the primary cause for its clinical inefficacy is chemoresistance. Here, we aimed to investigate a novel mechanism of chemoresistance in LUAD cells, focusing on the calcium-sensing receptor (CaSR). In this study, high CaSR expression was detected in DDP-resistant LUAD cells, and elevated CaSR expression is strongly correlated with poor prognosis in LUAD patients receiving chemotherapy. LUAD cells with high CaSR expression exhibited decreased sensitivity to cisplatin, and the growth of DDP-resistant LUAD cells was inhibited by cisplatin treatment in combination with CaSR suppression, accompanied by changes in BRCA1 and cyclin B1 protein expression both in vitro and in vivo. Additionally, an interaction between CaSR and KIF11 was identified. Importantly, suppressing KIF11 resulted in decreased protein levels of BRCA1 and cyclin B1, enhancing the sensitivity of DDP-resistant LUAD cells to cisplatin with no obvious decrease in CaSR. Here, our findings established the critical role of CaSR in promoting cisplatin resistance in LUAD cells by modulating cyclin B1 and BRCA1 and identified KIF11 as a mediator, highlighting the potential therapeutic value of targeting CaSR to overcome chemoresistance in LUAD.

钙传感受体与 KIF11 的相互作用通过 BRCA1/cyclin B1 途径增强了肺腺癌对顺铂的耐药性
顺铂(DDP)是治疗包括肺腺癌(LUAD)在内的非小细胞肺癌(NSCLC)的常用药物,其临床疗效不佳的主要原因是化疗耐药性。在此,我们以钙感受体(CaSR)为重点,旨在研究LUAD细胞化疗耐药的新机制。在这项研究中,DDP耐药的LUAD细胞中检测到了CaSR的高表达,而CaSR的高表达与接受化疗的LUAD患者的不良预后密切相关。CaSR高表达的LUAD细胞对顺铂的敏感性降低,顺铂治疗联合CaSR抑制可抑制DDP耐药LUAD细胞的生长,同时体外和体内BRCA1和细胞周期蛋白B1的表达也会发生变化。此外,还发现了 CaSR 与 KIF11 之间的相互作用。重要的是,抑制 KIF11 会导致 BRCA1 和细胞周期蛋白 B1 蛋白水平的降低,从而增强对 DDP 抗性的 LUAD 细胞对顺铂的敏感性,而 CaSR 并没有明显降低。在此,我们的研究结果确定了CaSR通过调节细胞周期蛋白B1和BRCA1在促进LUAD细胞对顺铂耐药中的关键作用,并确定了KIF11是一个介导因子,突出了靶向CaSR克服LUAD化疗耐药的潜在治疗价值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
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