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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.
摘要：
顺铂(DDP)常用于治疗非小细胞肺癌(NSCLC),包括肺腺癌（LUAD），其临床无效的主要原因是化疗耐药。这里,我们旨在研究LUAD细胞化学耐药的新机制，关注钙敏感受体（CaSR）。在这项研究中,在DDP抗性LUAD细胞中检测到高CaSR表达，在接受化疗的LUAD患者中，CaSR表达升高与预后不良密切相关。高CaSR表达的LUAD细胞对顺铂的敏感性降低，顺铂治疗联合CaSR抑制抑制DDP耐药的LUAD细胞的生长，同时伴有体内外BRCA1和细胞周期蛋白B1蛋白表达的变化。此外,确定了CaSR和KIF11之间的相互作用。重要的是,抑制KIF11导致BRCA1和cyclinB1蛋白水平降低，增强DDP抗性LUAD细胞对顺铂的敏感性，而CaSR无明显下降。这里,我们的发现确立了CaSR在通过调节细胞周期蛋白B1和BRCA1促进LUAD细胞顺铂耐药中的关键作用，并确定了KIF11作为介质，强调靶向CaSR克服LUAD化疗耐药的潜在治疗价值。
