HuR-targeted small molecule inhibitor exhibits cytotoxicity towards human lung cancer cells
dc.contributor.author | Muralidharan, Ranganayaki | |
dc.contributor.author | Mehta, Meghna | |
dc.contributor.author | Ahmed, Rebaz | |
dc.contributor.author | Roy, Sudeshna | |
dc.contributor.author | Xu, Liang | |
dc.contributor.author | Aubé, Jeffrey | |
dc.contributor.author | Chen, Allshine | |
dc.contributor.author | Zhao, Yan Daniel | |
dc.contributor.author | Herman, Terence | |
dc.contributor.author | Munshi, Anupama | |
dc.date.accessioned | 2018-11-16T22:27:33Z | |
dc.date.available | 2018-11-16T22:27:33Z | |
dc.date.issued | 2017-08-30 | |
dc.identifier.citation | Muralidharan, R., Mehta, M., Ahmed, R., Roy, S., Xu, L., Aubé, J., ... & Munshi, A. (2017). HuR-targeted small molecule inhibitor exhibits cytotoxicity towards human lung cancer cells. Scientific Reports, 7(1), 9694. | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/27398 | |
dc.description.abstract | Human antigen (Hu) R is an RNA-binding protein whose overexpression in human cancer correlates with aggressive disease, drug resistance, and poor prognosis. HuR inhibition has profound anticancer activity. Pharmacologic inhibitors can overcome the limitations of genetic inhibition. In this study, we examined the antitumor activity of CMLD-2, a small-molecule inhibitor directed against HuR, using non-small cell lung cancer (NSCLC) as a model. CMLD-2 efficacy was tested in vitro using H1299, A549, HCC827, and H1975 NSCLC cells and MRC-9 and CCD-16 normal human fibroblasts. Treatment of NSCLC cells with CMLD-2 produced dose-dependent cytotoxicity, caused a G1 phase cell-cycle arrest and induced apoptosis. CMLD-2 decreased HuR mRNA and the mRNAs of HuR-regulated proteins (Bcl2 and p27) in tumor cells. Additionally, reduction in the expression of HuR, Bcl2, cyclin E, and Bcl-XL with increased expression of Bax and p27 in CMLD-2-treated NSCLC cells were observed. CMLD-2-treated normal cells, HuR-regulated mRNAs and proteins albeit showed some reduction were less compared to tumor cells. Finally, CMLD-2 treatment resulted in greater mitochondrial perturbation, activation of caspase-9 and -3 and cleavage of PARP in tumor cells compared to normal cells. Our proof-of concept study results demonstrate CMLD-2 represents a promising HuR-targeted therapeutic class that with further development could lead to advanced preclinical studied and ultimately for lung cancer treatment. | en_US |
dc.description.sponsorship | R01 CA167516 | en_US |
dc.description.sponsorship | R01 CA191785 | en_US |
dc.description.sponsorship | P20 GM103639 | en_US |
dc.publisher | Nature Research | en_US |
dc.rights | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Cancer | en_US |
dc.subject | Non-small-cell lung cancer | en_US |
dc.title | HuR-targeted small molecule inhibitor exhibits cytotoxicity towards human lung cancer cells | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Xu, Liang | |
kusw.kudepartment | Molecular Biosciences | en_US |
dc.identifier.doi | 10.1038/s41598-017-07787-4 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-7658-5338 | en_US |
kusw.oaversion | Scholarly/refereed, publisher version | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.rights.accessrights | openAccess | en_US |
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