适配器蛋白CEMIP通过激活SRC-YAP致癌模块来降低小细胞肺癌的化学敏度
Adaptor protein CEMIP reduces the chemosensitivity of small cell lung cancer via activation of an SRC-YAP oncogenic module
影响因子:8.40000
分区:医学2区 / 药学1区 化学：综合2区
发表日期:2024 Dec
作者:
Xiao-Ju Shen, Hui-Lan Wei, Xiao-Cheng Mo, Xiao-Xiang Mo, Li Li, Jing-Chuan He, Xin-Yu Wei, Xiao-Jun Qin, Shang-Ping Xing, Zhuo Luo, Zhi-Quan Chen, Jie Yang
摘要
小细胞肺癌（SCLC）是一种顽固性恶性肿瘤，由于初始治疗反应后快速复发而预后衰退。迫切需要对SCLC的更有效的治疗方法。我们先前的研究表明，诱导细胞迁移的透明质酸结合蛋白（CEMIP）在功能上促进了SCLC细胞增殖和转移。在这项研究中，我们研究了CEMIP是否以及如何调节SCLC的化学敏度。通过GDSC数据库，我们发现CEMIP表达水平与SCLC细胞中几种常用化学治疗药物的IC50值呈正相关（顺铂，吉西他滨，5-氟尿嘧啶和环磷酰胺）。我们证明，SCLC细胞中CEMIP的过表达或敲低分别导致顺铂或依托泊苷的IC50值显着增加或降低。我们进一步揭示了CEMIP在SCLC细胞中用作适配器蛋白，通过1-177 AA结构域和820-1361 AA结构域与SRC和YAP相互作用，允许Y416的自动磷酸化和SRC的激活，从而促进YAP和激活的SRC和激活的速率，从而促进了YAP的相互作用，从而增加了YAP的相互作用。 YAP的积累和转录激活。过表达的SRC或YAP抵消了CEMIP敲低介导的SCLC细胞对顺铂和依托泊苷的敏感性的增加。 SRC抑制剂dasatinib或YAP抑制剂Verteporfin和顺铂/依托泊苷（EP方案）的组合表现出极好的协同抗肿瘤对体外和体内SCLC的影响。这项研究表明，针对CEMIP/SRC/YAP复合物的有针对性治疗是SCLC的潜在策略，并为开发具有转化前景的未来临床试验提供了理由。
Abstract
Small cell lung cancer (SCLC) is a recalcitrant malignancy with dismal prognosis due to rapid relapse after an initial treatment response. More effective treatments for SCLC are desperately needed. Our previous studies showed that cell migration-inducing hyaluronan binding protein (CEMIP) functionally promotes SCLC cell proliferation and metastasis. In this study, we investigated whether and how CEMIP regulates the chemosensitivity of SCLC. Through the GDSC database, we found that CEMIP expression levels were positively correlated with the IC50 values of several commonly used chemotherapeutic drugs in SCLC cells (cisplatin, gemcitabine, 5-fluorouracil and cyclophosphamide). We demonstrated that overexpression or knockdown of CEMIP in SCLC cells resulted in a notable increase or reduction in the IC50 value of cisplatin or etoposide, respectively. We further revealed that CEMIP functions as an adaptor protein in SCLC cells to interact with SRC and YAP through the 1-177 aa domain and 820-1361 aa domain, respectively, allowing the autophosphorylation of Y416 and activation of SRC, thus facilitating the interaction between YAP and activated SRC, and resulting in increased phosphorylation of Y357, protein stability, nuclear accumulation and transcriptional activation of YAP. Overexpressing SRC or YAP counteracted the CEMIP knockdown-mediated increase in the sensitivity of SCLC cells to cisplatin and etoposide. The combination of the SRC inhibitor dasatinib or the YAP inhibitor verteporfin and cisplatin/etoposide (EP regimen) displayed excellent synergistic antitumor effects on SCLC both in vitro and in vivo. This study demonstrated that targeted therapy against the CEMIP/SRC/YAP complex is a potential strategy for SCLC and provides a rationale for the development of future clinical trials with translational prospects.