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The Indole Rocaglamide Induces S and G2/M Phase Cell Cycle Arrest in Small Cell Lung Cancer Cells Through ASCL1 Translation Inhibition

68 Pages Posted: 30 Jun 2023 Publication Status: Review Complete

See all articles by Midori Arai

Midori Arai

Keio University - Faculty of Science & Technology

Yoshinori Makita

Chiba University - Graduate School of Pharmaceutical Sciences

Shun Saito

Keio University - Faculty of Science & Technology

Shiina Suzuki

Keio University - Faculty of Science & Technology

Yuki Narushima

Keio University - Faculty of Science & Technology

Nanoha Izawa

Keio University - Faculty of Science & Technology

Yuki Tanaka

Chiba University - Graduate School of Pharmaceutical Sciences

Kairi Furui

Tokyo Institute of Technology - Department of Computer Science

Masahito Ohue

Tokyo Institute of Technology - Department of Computer Science

Masami Ishibashi

Chiba University - Graduate School of Pharmaceutical Sciences

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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.

Note:
Funding Information: We thank Prof. R. Kageyama for providing cells for ASCL1 inhibition assays. This study was supported by a Grant-in-Aid for Scientific Research (B) (21H02639 [M.A.A.]) from the Japan Society for the Promotion of Science (JSPS) and a Grant-in-Aid for Transformative Research Area (A) “Latent Chemical Space” (23H04880 [M.A.A. and M.O.], 23H04884 [M.A.A.] and 23H04887 [M.O.]) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Declaration of Interests: The authors have declared that no competing interest exists.

Suggested Citation

Arai, Midori and Makita, Yoshinori and Saito, Shun and Suzuki, Shiina and Narushima, Yuki and Izawa, Nanoha and Tanaka, Yuki and Furui, Kairi and Ohue, Masahito and Ishibashi, Masami, The Indole Rocaglamide Induces S and G2/M Phase Cell Cycle Arrest in Small Cell Lung Cancer Cells Through ASCL1 Translation Inhibition. Available at SSRN: https://ssrn.com/abstract=4493242 or http://dx.doi.org/10.2139/ssrn.4493242
This version of the paper has not been formally peer reviewed.

Midori Arai (Contact Author)

Keio University - Faculty of Science & Technology ( email )

Yoshinori Makita

Chiba University - Graduate School of Pharmaceutical Sciences ( email )

Shun Saito

Keio University - Faculty of Science & Technology ( email )

Shiina Suzuki

Keio University - Faculty of Science & Technology ( email )

Yuki Narushima

Keio University - Faculty of Science & Technology ( email )

Nanoha Izawa

Keio University - Faculty of Science & Technology ( email )

Yuki Tanaka

Chiba University - Graduate School of Pharmaceutical Sciences ( email )

Kairi Furui

Tokyo Institute of Technology - Department of Computer Science ( email )

Masahito Ohue

Tokyo Institute of Technology - Department of Computer Science ( email )

Masami Ishibashi

Chiba University - Graduate School of Pharmaceutical Sciences ( email )

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