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Identification and Validation of an Aspergillus nidulans Secondary Metabolite Derivative as an Inhibitor of the Musashi-RNA Interaction
Lan, Lan Liu, Jiajun Xing, Minli Smith, Amber R. Wang, Jinan Wu, Xiaoqing Appelman, Carl Li, Ke Roy, Anuradha Gowthaman, Ragul
Lan, Lan
Liu, Jiajun
Xing, Minli
Smith, Amber R.
Wang, Jinan
Wu, Xiaoqing
Appelman, Carl
Li, Ke
Roy, Anuradha
Gowthaman, Ragul
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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.
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This work is licensed under a Creative Commons Attribution 4.0 International License.
Date
2020-08-08
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Publisher
Wiley
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Keywords
RNA-binding proteins, Musashi, Drug discovery, Notch signaling, Wnt signaling, Cancer therapy, Fungi secondary metabolite derivative
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