2. Academic Validation
  3. Adaptor protein CEMIP reduces the chemosensitivity of small cell lung cancer via activation of an SRC-YAP oncogenic module

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

  • Acta Pharmacol Sin. 2024 Jul 23. doi: 10.1038/s41401-024-01342-4.
Xiao-Ju Shen # 1 2,  Hui-Lan Wei # 1,  Xiao-Cheng Mo # 1 2,  Xiao-Xiang Mo 3,  Li Li 4,  Jing-Chuan He 1,  Xin-Yu Wei 1,  Xiao-Jun Qin 5,  Shang-Ping Xing 6,  Zhuo Luo 7,  Zhi-Quan Chen 8,  Jie Yang 9 10 11
Affiliations

Affiliations

  • 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 Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning, 530021, China. luozhuo@gxmu.edu.cn.
  • 8 Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning, 530021, China. chenzhiquan@stu.gxmu.edu.cn.
  • 9 Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning, 530021, China. jieyang2016@gxmu.edu.cn.
  • 10 Guangxi Key Laboratory of Drug Basic Research for Prevention and Treatment of Geriatric Diseases, School of Pharmacy, Guangxi Medical University, Nanning, 530021, China. jieyang2016@gxmu.edu.cn.
  • 11 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. jieyang2016@gxmu.edu.cn.
  • # Contributed equally.
PMID: 39043968 DOI: 10.1038/s41401-024-01342-4
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.

Keywords

CEMIP; SRC; YAP; adaptor protein; chemotherapy sensitivity; small cell lung cancer.

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