RNA binding proteins have emerged as critical oncogenic factors and potential targets in cancer therapy. In this study, we evaluated Musashi1 (Msi1) targeting as a strategy to treat glioblastoma (GBM); the most aggressive brain tumor type. Msi1 expression levels are often high in GBMs and other tumor types and correlate with poor clinical outcome. Moreover, Msi1 has been implicated in chemo- and radio-resistance. Msi1 modulates a range of cancer relevant processes and pathways and regulates the expression of stem cell markers and oncogenic factors via mRNA translation/stability. To identify Msi1 inhibitors capable of blocking its RNA binding function, we performed a ~25,000 compound fluorescence polarization screen. NMR and LSPR were used to confirm direct interaction between Msi1 and luteolin, the leading compound. Luteolin displayed strong interaction with Msi1 RNA binding domain 1 (RBD1). As a likely consequence of this interaction, we observed via western and luciferase assays that luteolin treatment diminished Msi1 positive impact on the expression of pro-oncogenic target genes. We tested the effect of luteolin treatment on GBM cells and showed that it reduced proliferation, cell viability, colony formation, migration and invasion of U251 and U343 GBM cells. Luteolin also decreased the proliferation of patient-derived glioma initiating cells (GICs) and tumor-organoids but did not affect normal astrocytes. Finally, we demonstrated the value of combined treatments with luteolin and olaparib (PARP inhibitor) or ionizing radiation (IR). Our results show that luteolin functions as an inhibitor of Msi1 and demonstrates its potential use in GBM therapy.
Funding
This work was supported by grants from Voices Against Brain Tumor and Greehey Children’s Cancer Research Institute. Caihong Yi was sponsored by the Second Xiangya Hospital of Central South University (CSU). The work performed in the Center for Innovative Drug Discovery was supported, in part, by the National Center for Advancing Translational Sciences, National Institutes of Health, under Grant UL1 TR001120. Christopher Hubert was supported by NIH under grant F32CA18964701 and by the Center for Transformational Nanoscience. The authors would also like to acknowledge the grant support (RP160884) from the Cancer Prevention and Research Institute of Texas. The Institutional NMR Core Facility at the UT Health San Antonio is supported in part as a Shared Resource of the NIH P30 CA054174 to the Mays Cancer Center - UT Health San Antonio;<#funding-source;>National Cancer InstituteAU: Please note that the Funder name National Cancer Institute has been created from information provided through CATS. Please confirm if the Funding section is accurate. [<#award-id;>UL1 TR001120];<#funding-source;>National Cancer InstituteAU: Please note that the Funder name National Cancer Institute has been created from information provided through CATS. Please confirm if the Funding section is accurate. [<#award-id;>F32CA18964701];<#funding-source;>GCCRI-UTHSCSAAU: The funding information GCCRI-UTHSCSA provided has been checked against the Open Funder Registry and we failed to find a match. Please confirm if the Funding section is accurate and also confirm the funder name GCCRI-UTHSCSA. [<#award-id;>NA];<#funding-source;>CPRITAU: The funding information CPRIT provided has been checked against the Open Funder Registry and we failed to find a match. Please confirm if the Funding section is accurate and also confirm the funder name CPRIT. [<#award-id;>RP160884];<#funding-source;>Voices Against Brain CancerAU: Please note that the Funder name Voices Against Brain Cancer has been created from in
