dc.contributor.author | Lan, Lan | |
dc.contributor.author | Liu, Jiajun | |
dc.contributor.author | Xing, Minli | |
dc.contributor.author | Smith, Amber R. | |
dc.contributor.author | Wang, Jinan | |
dc.contributor.author | Wu, Xiaoqing | |
dc.contributor.author | Appelman, Carl | |
dc.contributor.author | Li, Ke | |
dc.contributor.author | Roy, Anuradha | |
dc.contributor.author | Gowthaman, Ragul | |
dc.contributor.author | Karanicolas, John | |
dc.contributor.author | Somoza, Amber D. | |
dc.contributor.author | Wang, Clay C. C. | |
dc.contributor.author | Miao, Yinglong | |
dc.contributor.author | Guzman, Roberto De | |
dc.contributor.author | Oakley, Berl R. | |
dc.contributor.author | Neufeld, Kristi L. | |
dc.contributor.author | Xu, Liang | |
dc.date.accessioned | 2020-11-10T21:21:41Z | |
dc.date.available | 2020-11-10T21:21:41Z | |
dc.date.issued | 2020-08-08 | |
dc.identifier.citation | Lan, L., Liu, J., Xing, M., Smith, A. R., Wang, J., Wu, X., Appelman, C., Li, K., Roy, A., Gowthaman, R., Karanicolas, J., Somoza, A. D., Wang, C., Miao, Y., De Guzman, R., Oakley, B. R., Neufeld, K. L., & Xu, L. (2020). Identification and Validation of an Aspergillus nidulans Secondary Metabolite Derivative as an Inhibitor of the Musashi-RNA Interaction. Cancers, 12(8), 2221. https://doi.org/10.3390/cancers12082221 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/30822 | |
dc.description | This work is licensed under a Creative Commons Attribution 4.0 International License. | en_US |
dc.description.abstract | RNA-binding protein Musashi-1 (MSI1) is a key regulator of several stem cell populations. MSI1 is involved in tumor proliferation and maintenance, and it regulates target mRNAs at the translational level. The known mRNA targets of MSI1 include Numb, APC, and P21WAF-1, key regulators of Notch/Wnt signaling and cell cycle progression, respectively. In this study, we aim to identify small molecule inhibitors of MSI1–mRNA interactions, which could block the growth of cancer cells with high levels of MSI1. Using a fluorescence polarization (FP) assay, we screened small molecules from several chemical libraries for those that disrupt the binding of MSI1 to its consensus RNA. One cluster of hit compounds is the derivatives of secondary metabolites from Aspergillus nidulans. One of the top hits, Aza-9, from this cluster was further validated by surface plasmon resonance and nuclear magnetic resonance spectroscopy, which demonstrated that Aza-9 binds directly to MSI1, and the binding is at the RNA binding pocket. We also show that Aza-9 binds to Musashi-2 (MSI2) as well. To test whether Aza-9 has anti-cancer potential, we used liposomes to facilitate Aza-9 cellular uptake. Aza-9-liposome inhibits proliferation, induces apoptosis and autophagy, and down-regulates Notch and Wnt signaling in colon cancer cell lines. In conclusion, we identified a series of potential lead compounds for inhibiting MSI1/2 function, while establishing a framework for identifying small molecule inhibitors of RNA binding proteins using FP-based screening methodology. | en_US |
dc.description.sponsorship | NIH R01 CA178831 | en_US |
dc.description.sponsorship | NIH CA191785 | en_US |
dc.description.sponsorship | National Institute of General Medical Science (P01GM084077) | en_US |
dc.description.sponsorship | University of Kansas Bold Aspiration Strategic Initiative Award | en_US |
dc.description.sponsorship | National Cancer Institute Cancer Center Support Grant P30 CA168524 | en_US |
dc.description.sponsorship | Kansas Bioscience Authority Rising Star Award | en_US |
dc.description.sponsorship | NIH AI074856 | en_US |
dc.description.sponsorship | NIH COBRE | en_US |
dc.description.sponsorship | Irving S. Johnson Fund of the University of Kansas Endowment | en_US |
dc.publisher | Wiley | en_US |
dc.rights | © 2020 by the authors. Licensee MDPI, Basel, Switzerland. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | RNA-binding proteins | en_US |
dc.subject | Musashi | en_US |
dc.subject | Drug discovery | en_US |
dc.subject | Notch signaling | en_US |
dc.subject | Wnt signaling | en_US |
dc.subject | Cancer therapy | en_US |
dc.subject | Fungi secondary metabolite derivative | en_US |
dc.title | Identification and Validation of an Aspergillus nidulans Secondary Metabolite Derivative as an Inhibitor of the Musashi-RNA Interaction | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Lan, Lan | |
kusw.kuauthor | Liu, Jiajun | |
kusw.kuauthor | Xing, Minli | |
kusw.kuauthor | Smith, Amber R. | |
kusw.kuauthor | Wang, Jinan | |
kusw.kuauthor | Wu, Xiaoqing | |
kusw.kuauthor | Appelman, Carl | |
kusw.kuauthor | Li, Ke | |
kusw.kuauthor | Roy, Anuradha | |
kusw.kuauthor | Gowthaman, Ragul | |
kusw.kuauthor | Miao, Yinglong | |
kusw.kuauthor | Guzman, Roberto De | |
kusw.kuauthor | Oakley, Berl R. | |
kusw.kuauthor | Neufeld, Kristi L. | |
kusw.kuauthor | Xu, Liang | |
kusw.kudepartment | Molecular Biosciences | en_US |
kusw.kudepartment | Bio-NMR Core Facility | en_US |
kusw.kudepartment | Center for Computational Biology | en_US |
kusw.kudepartment | High Throughput Screening Laboratory | en_US |
dc.identifier.doi | 10.3390/cancers12082221 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-8045-7654 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0003-0162-212X | en_US |
dc.identifier.orcid | https://orcid.org/0000-0003-0300-726X | en_US |
dc.identifier.orcid | https://orcid.org/0000-0003-3653-9385 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0001-9196-4232 | en_US |
kusw.oaversion | Scholarly/refereed, publisher version | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC7463734 | en_US |
dc.rights.accessrights | openAccess | en_US |