دورية أكاديمية
Rolapitant treats lung cancer by targeting deubiquitinase OTUD3
| العنوان: | Rolapitant treats lung cancer by targeting deubiquitinase OTUD3 |
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| المؤلفون: | Tongde Du, Quan Gu, Yonghui Zhang, Yujie Gan, Rongrui Liang, Wenzhu Yang, Ya Lu, Chenxin Xu, Jianzhong Wu, Rong Ma, Haixia Cao, Jingwei Jiang, Juan Wang, Jifeng Feng |
| المصدر: | Cell Communication and Signaling, Vol 22, Iss 1, Pp 1-21 (2024) |
| بيانات النشر: | BMC, 2024. |
| سنة النشر: | 2024 |
| المجموعة: | LCC:Medicine LCC:Cytology |
| مصطلحات موضوعية: | Lung cancer, OTUD3, DR5, Rolapitant, Inhibitor, Apoptosis, Medicine, Cytology, QH573-671 |
| الوصف: | Abstract Background Lung cancer is cancer with the highest morbidity and mortality in the world and poses a serious threat to human health. Therefore, discovering new treatments is urgently needed to improve lung cancer prognosis. Small molecule inhibitors targeting the ubiquitin-proteasome system have achieved great success, in which deubiquitinase inhibitors have broad clinical applications. The deubiquitylase OTUD3 was reported to promote lung tumorigenesis by stabilizing oncoprotein GRP78, implying that inhibition of OTUD3 may be a therapeutic strategy for lung cancer. Results In this study, we identified a small molecule inhibitor of OTUD3, Rolapitant, by computer-aided virtual screening and biological experimental verification from FDA-approved drugs library. Rolapitant inhibited the proliferation of lung cancer cells by inhibiting deubiquitinating activity of OTUD3. Quantitative proteomic profiling indicated that Rolapitant significantly upregulated the expression of death receptor 5 (DR5). Rolapitant also promoted lung cancer cell apoptosis through upregulating cell surface expression of DR5 and enhanced TRAIL-induced apoptosis. Mechanistically, Rolapitant directly targeted the OTUD3-GRP78 axis to trigger endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP)-DR5 signaling, sensitizing lung cancer cells to TRAIL-induced apoptosis. In the vivo assays, Rolapitant suppressed the growth of lung cancer xenografts in immunocompromised mice at suitable dosages without apparent toxicity. Conclusion In summary, the present study identifies Rolapitant as a novel inhibitor of deubiquitinase OTUD3 and establishes that the OTUD3-GRP78 axis is a potential therapeutic target for lung cancer. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1478-811X |
| Relation: | https://doaj.org/toc/1478-811X |
| DOI: | 10.1186/s12964-024-01519-8 |
| URL الوصول: | https://doaj.org/article/d0f30f0c07644780b90b359331943424 |
| رقم الأكسشن: | edsdoj.0f30f0c07644780b90b359331943424 |
| قاعدة البيانات: | Directory of Open Access Journals |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 1478811X |
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| DOI: | 10.1186/s12964-024-01519-8 |