Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis

// Fernando F. Blanco 1, 5 , Ranjan Preet 1 , Andrea Aguado 1 , Vikalp Vishwakarma 1 , Laura E. Stevens 1 , Alok Vyas 6 , Subhash Padhye 6 , Liang Xu 4, 7 , Scott J. Weir 2, 4 , Shrikant Anant 3, 4 , Nicole Meisner-Kober 8 , Jonathan R. Brody 5 , Dan A. Dixon 1, 4 1 Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA 2 Department of Pharmacology, University of Kansas Medical Center, Kansas City, KS, USA 3 Department of Surgery, University of Kansas Medical Center, Kansas City, KS, USA 4 University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA 5 Department of Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA 6 Maharashtra Cosmopolitan Education Society's ISTRA, Azam Campus, University of Pune, India 7 Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA 8 Novartis Institutes for Biomedical Research, Basel, Switzerland Correspondence to: Jonathan R. Brody, email: Jonathan.Brody@jefferson.edu Dan A. Dixon, email: ddixon3@kumc.edu Keywords: HuR, MS-444, AU-rich elements, RNA stability, colon cancer Received: May 02, 2016      Accepted: August 11, 2016      Published: September 22, 2016 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.