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

• Published in: Oncotarget 2016-11, Vol.7 (45), p.74043-74058
• Main Authors: Blanco, Fernando F, Preet, Ranjan, Aguado, Andrea, Vishwakarma, Vikalp, Stevens, Laura E, Vyas, Alok, Padhye, Subhash, Xu, Liang, Weir, Scott J, Anant, Shrikant, Meisner-Kober, Nicole, Brody, Jonathan R, Dixon, Dan A
• Format: Article
• Language: English
• Subjects: Animals; Carcinogenesis; Cell Line, Tumor; Cell Proliferation - drug effects; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - pharmacology; ELAV-Like Protein 1 - antagonists & inhibitors; ELAV-Like Protein 1 - metabolism; Furans - pharmacology; HCT116 Cells; HT29 Cells; Humans; Mice; Mice, Nude; Naphthols - pharmacology; Research Paper; Transfection; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.12189

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.