Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis
dc.contributor.author | Blanco, Fernando F. | |
dc.contributor.author | Preet, Ranjan | |
dc.contributor.author | Aguado, Andrea | |
dc.contributor.author | Vishwakarma, Vikalp | |
dc.contributor.author | Stevens, Laura E. | |
dc.contributor.author | Vyas, Alok | |
dc.contributor.author | Padhye, Subhash | |
dc.contributor.author | Xu, Liang | |
dc.contributor.author | Weir, Scott J. | |
dc.contributor.author | Anant, Shrikant | |
dc.contributor.author | Meisner-Kober, Nicole | |
dc.contributor.author | Brody, Jonathan R. | |
dc.contributor.author | Dixon, Dan A. | |
dc.date.accessioned | 2017-09-22T17:32:11Z | |
dc.date.available | 2017-09-22T17:32:11Z | |
dc.date.issued | 2016-09-22 | |
dc.identifier.citation | Blanco, F. F., Preet, R., Aguado, A., Vishwakarma, V., Stevens, L. E., Vyas, A., … Dixon, D. A. (2016). Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis. Oncotarget, 7(45), 74043–74058. http://doi.org/10.18632/oncotarget.12189 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/25001 | |
dc.description.abstract | Colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer-related mortality. Observed during CRC tumorigenesis is loss of post-transcriptional regulation of tumor-promoting genes such as COX-2, TNFα and VEGF. Overexpression of the RNA-binding protein HuR (ELAVL1) occurs during colon tumorigenesis and is abnormally present within the cytoplasm, where it post-transcriptionally regulates genes through its interaction with 3′UTR AU-rich elements (AREs). Here, we examine the therapeutic potential of targeting HuR using MS-444, a small molecule HuR inhibitor. Treatment of CRC cells with MS-444 resulted in growth inhibition and increased apoptotic gene expression, while similar treatment doses in non-transformed intestinal cells had no appreciable effects. Mechanistically, MS-444 disrupted HuR cytoplasmic trafficking and released ARE-mRNAs for localization to P-bodies, but did not affect total HuR expression levels. This resulted in MS-444-mediated inhibition of COX-2 and other ARE-mRNA expression levels. Importantly, MS-444 was well tolerated and inhibited xenograft CRC tumor growth through enhanced apoptosis and decreased angiogenesis upon intraperitoneal administration. In vivo treatment of MS-444 inhibited HuR cytoplasmic localization and decreased COX-2 expression in tumors. These findings provide evidence that therapeutic strategies to target HuR in CRC warrant further investigation in an effort to move this approach to the clinic. | en_US |
dc.publisher | Impact Journals | en_US |
dc.rights | This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | HuR | en_US |
dc.subject | MS-444 | en_US |
dc.subject | AU-rich elements | en_US |
dc.subject | RNA stability | en_US |
dc.subject | Colon cancer | en_US |
dc.title | Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Xu, Liang | |
kusw.kudepartment | Molecular Biosciences | en_US |
dc.identifier.doi | 10.18632/oncotarget.12189 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0001-5555-2126 | |
kusw.oaversion | Scholarly/refereed, publisher version | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC5342034 | en_US |
dc.rights.accessrights | openAccess |
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