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

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 

机构地区：[1]Department of Pharmacology,School of Pharmacy,Guangxi Medical University,Nanning 530021,China [2]Department of Pharmacy,The First Affiliated Hospital of Guangxi Medical University,Nanning 530021,China [3]Department of Pharmacology,Maternity and Child Health Care of Guangxi Zhuang Autonomous Region,Nanning 530021,China [4]Department of Pharmacology,Guangxi Institute of Chinese Medicine&Pharmaceutical Science,Nanning 530001,China [5]Department of Pharmaceutical Analysis,School of Pharmacy,Guangxi Medical University,Nanning 530021,China [6]Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation,School of Pharmacy,Guangxi Medical University,Nanning 530021,China [7]Guangxi Key Laboratory of Drug Basic Research for Prevention and Treatment of Geriatric Diseases,School of Pharmacy,Guangxi Medical University,Nanning 530021,China [8]The Laboratory of Toxicology of Traditional Chinese Medicine,Leve III Laboratory of National Administration of Traditional Chinese Medicine,School of Pharmacy,Guangxi Medical University,Nanning 530021,China

出　　处：《Acta Pharmacologica Sinica》2024年第12期2657-2671,共15页中国药理学报（英文版）

基　　金：supported by National Natural Science Foundation of China(82374093);Joint Project on Regional High-lncidence Diseases Research of Guangxi Natural Science Foundation under Grant No.2023GXNSFDA026026;National Natural Science Foundation of China(82160698);Joint Project on Regional High-lncidence Diseases Research of Guangxi Natural Science Foundation under Grant No.2024GXNSFBA010027;Guangxi Natural Science Foundation(No.2022GXNSFBA035652);The Science and Technology Planning Project of Nanning Qingxiu District(No:2021013);the Guangxi Medical University Training Program for Distinguished Young Scholars,and the Guangxi First-class Discipline Project for Pharmaceutical Sciences(No.GXFCDP-PS-2018)。

摘　　要：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.

关 键 词：small cell lung cancer CEMIP adaptor protein SRC YAP chemotherapy sensitivity 

分 类 号：R734.2[医药卫生—肿瘤]