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

Fernando F. Blanco, Ranjan Preet, Andrea Aguado, Vikalp Vishwakarma, Laura E. Stevens, Alok Vyas, Subhash Padhye, Liang Xu, Scott J. Weir, Shrikant Anant, Nicole Meisner-Kober, Jonathan R. Brody, Dan A. Dixon

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

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 posttranscriptional regulation of tumor-promoting genes such as COX-2, TNFa and VEGF. Overexpression of the RNA-binding protein HuR (ELAVL1) occurs during colon tumorigenesis and is abnormally present within the cytoplasm, where it posttranscriptionally 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.

Original languageEnglish (US)
Pages (from-to)74043-74058
Number of pages16
JournalOncotarget
Volume7
Issue number45
DOIs
StatePublished - 2016
Externally publishedYes

Keywords

  • AU-rich elements
  • Colon cancer
  • HuR
  • MS-444
  • RNA stability

ASJC Scopus subject areas

  • Oncology

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