Identification and Validation of an Aspergillus nidulans Secondary Metabolite Derivative as an Inhibitor of the Musashi-RNA Interaction
Open Access
- 7 August 2020
- Vol. 12 (8), 2221
- https://doi.org/10.3390/cancers12082221
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.Funding Information
- National Institutes of Health (R01 CA178831, R01 CA191785, AI074856)
- National Institute of General Medical Science (P01GM084077)
- The University of Kansas (Bold Aspiration Strategic Initiative Award)
- Kansas Bioscience Authority (Rising Star Award)
This publication has 62 references indexed in Scilit:
- Reengineering an Azaphilone Biosynthesis Pathway in Aspergillus nidulans To Create Lipoxygenase InhibitorsOrganic Letters, 2012
- Structure of Musashi1 in a complex with target RNA: the role of aromatic stacking interactionsNucleic Acids Research, 2011
- Novel Double-negative Feedback Loop between Adenomatous Polyposis Coli and Musashi1 in Colon EpitheliaOnline Journal of Public Health Informatics, 2011
- Regulation of myeloid leukaemia by the cell-fate determinant MusashiNature, 2010
- Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemiaNature Medicine, 2010
- Design and synthesis of novel Gefitinib analogues with improved anti-tumor activityBioorganic & Medicinal Chemistry, 2010
- Expression of putative stem cell genes Musashi-1 and β1-integrin in human colorectal adenomas and adenocarcinomasInternational Journal of Colorectal Disease, 2009
- The Hantavirus Glycoprotein G1 Tail Contains Dual CCHC-type Classical Zinc FingersOnline Journal of Public Health Informatics, 2009
- Natural BH3 mimetic (-)-gossypol chemosensitizes human prostate cancer via Bcl-xL inhibition accompanied by increase of Puma and NoxaMolecular Cancer Therapeutics, 2008
- Musashi regulates the temporal order of mRNA translation during Xenopus oocyte maturationThe EMBO Journal, 2006