适配蛋白CEMIP通过激活SRC-YAP致癌模块降低小细胞肺癌的化疗敏感性

Adaptor protein CEMIP reduces the chemosensitivity of small cell lung cancer via activation of an SRC-YAP oncogenic module

ACTA PHARMACOLOGICA SINICA

影响因子:8.4

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

DOI: 10.1038/s41401-024-01342-4

摘要

小细胞肺癌（SCLC）是一种难治性恶性肿瘤，预后极差，主要因在初次治疗后迅速复发。迫切需要更有效的治疗策略。我们之前的研究显示，细胞迁移诱导的透明质酸结合蛋白（CEMIP）功能性促进SCLC细胞的增殖和转移。本研究探讨了CEMIP是否及如何调控SCLC的化疗敏感性。通过GDSC数据库发现，CEMIP的表达水平与多种常用化疗药物（顺铂、吉西他滨、5-氟尿嘧啶和环磷酰胺）的IC50值呈正相关。实验结果表明，过表达或敲低CEMIP在SCLC细胞中分别导致顺铂或依托泊苷的IC50值显著增加或减少。进一步揭示，CEMIP作为适配蛋白在SCLC细胞中与SRC和YAP相互作用，分别通过1-177氨基酸域和820-1361氨基酸域实现，激活Y416自磷酸化和SRC的激活，从而促进YAP与激活的SRC的相互作用，并增强YAP的Y357磷酸化、蛋白稳定性、核内积累及转录激活。过表达SRC或YAP能逆转CEMIP敲低引起的SCLC细胞对顺铂和依托泊苷敏感性的增加。结合SRC抑制剂达沙替尼或YAP抑制剂维拉帕菲林与顺铂/依托泊苷（EP方案）在体内外对SCLC表现出极佳的协同抗肿瘤效果。本研究证明针对CEMIP/SRC/YAP复合物的靶向治疗是SCLC的潜在策略，并为未来临床试验提供了转化依据。

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.