Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis
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Fernando F. Blanco1,5, Ranjan Preet1, Andrea Aguado1, Vikalp Vishwakarma1, Laura E. Stevens1, Alok Vyas6, Subhash Padhye6, Liang Xu4,7, Scott J. Weir2,4, Shrikant Anant3,4, Nicole Meisner-Kober8, Jonathan R. Brody5, Dan A. Dixon1,4
1Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
2Department of Pharmacology, University of Kansas Medical Center, Kansas City, KS, USA
3Department of Surgery, University of Kansas Medical Center, Kansas City, KS, USA
4University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA
5Department of Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
6Maharashtra Cosmopolitan Education Society's ISTRA, Azam Campus, University of Pune, India
7Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA
8Novartis Institutes for Biomedical Research, Basel, Switzerland
Jonathan R. Brody, email: [email protected]
Dan A. Dixon, email: [email protected]
Keywords: HuR, MS-444, AU-rich elements, RNA stability, colon cancer
Received: May 02, 2016 Accepted: August 11, 2016 Published: September 22, 2016
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.
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