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Title
Japanese: 
English:The Indole Rocaglamide Induces S and G2/M Phase Cell Cycle Arrest in Small Cell Lung Cancer Cells Through ASCL1 Translation Inhibition 
Author
Japanese: Midori Arai, Yoshinori Makita, Shun Saito, Shiina Suzuki, Yuki Narushima, Nanoha Izawa, Yuki Tanaka, 古井 海里, 大上 雅史, Masami Ishibashi.  
English: Midori Arai, Yoshinori Makita, Shun Saito, Shiina Suzuki, Yuki Narushima, Nanoha Izawa, Yuki Tanaka, Kairi Furui, Masahito Ohue, Masami Ishibashi.  
Language English 
Journal/Book name
Japanese: 
English: 
Volume, Number, Page        
Published date 2024 
Publisher
Japanese: 
English:SSRN preprint 
Conference name
Japanese: 
English: 
Conference site
Japanese: 
English: 
Official URL https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4493242
 
DOI https://doi.org/10.2139/ssrn.4493242
Abstract SUMMARYAchaete-scute homologue 1 (ASCL1) is a transcriptional factor related to small cell lung cancer (SCLC) development. Because ASCL1 inhibition suppresses cancer development, targeting ASCL1 would be effective for the treatment of SCLC. We focused on the natural product rocaglamide, a synthetic compound, and identified indole rocaglamide (−)-4k as a strong inhibitor of ASCL1. Elucidation of the underlying mechanism revealed that translation of ASCL1 is inhibited through the interaction of (−)-4k with eukaryotic initiation factor 4A and the 5’UTR of ASCL1 mRNA like a molecular glue. Also, (−)-4k induced S and G2/M arrest in SCLC cells via suppression of POLA2, which is downstream of ASCL1. Deletion of POLA2 caused DNA replication stress, which led phosphorylated check-point kinases to phosphorylate CDK1, causing S and G2/M arrest in SCLC cells. This is the first report of such a strong ASCL1 inhibitor and elucidation of cytotoxicity mechanism after inhibition of ASCL1. This study found that inhibiting the translation of ASCL1 using rocaglamide is effective for suppressing SCLC.

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