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 language | English (US) |
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Pages (from-to) | 74043-74058 |
Number of pages | 16 |
Journal | Oncotarget |
Volume | 7 |
Issue number | 45 |
DOIs | |
State | Published - 2016 |
Externally published | Yes |
Keywords
- AU-rich elements
- Colon cancer
- HuR
- MS-444
- RNA stability
ASJC Scopus subject areas
- Oncology