Wang Fuhao, Fu Xing, Chang Ming, Wei Tianzi, Lin Risheng, Tong Haibo, Zhang Xiao, Yuan Runzhu, Zhou Zhiqing, Huang Xin, Zhang Wei, Su Wenmei, Lu Yi, Liang Zhen, Zhang Jian
School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
The First Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
Int J Biol Sci. 2024 Jul 15;20(10):3892-3910. doi: 10.7150/ijbs.92046. eCollection 2024.
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 and . 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.
顺铂（DDP）常用于治疗非小细胞肺癌（NSCLC），包括肺腺癌（LUAD），其临床疗效不佳的主要原因是化疗耐药。在此，我们旨在研究LUAD细胞中一种新的化疗耐药机制，重点关注钙敏感受体（CaSR）。在本研究中，在顺铂耐药的LUAD细胞中检测到高CaSR表达，并且CaSR表达升高与接受化疗的LUAD患者的不良预后密切相关。高CaSR表达的LUAD细胞对顺铂的敏感性降低，顺铂治疗联合CaSR抑制可抑制顺铂耐药LUAD细胞的生长，同时伴随BRCA1和细胞周期蛋白B1蛋白表达的变化。此外，还鉴定出CaSR与KIF11之间存在相互作用。重要的是，抑制KIF11导致BRCA1和细胞周期蛋白B1的蛋白水平降低，增强了顺铂耐药LUAD细胞对顺铂的敏感性，而CaSR没有明显降低。在此，我们的研究结果确立了CaSR通过调节细胞周期蛋白B1和BRCA1在促进LUAD细胞顺铂耐药中的关键作用，并确定KIF11为介导因子，突出了靶向CaSR克服LUAD化疗耐药的潜在治疗价值。
