Dataset Information

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

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, TNF? 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.

SUBMITTER: Blanco FF

PROVIDER: S-EPMC5342034 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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

Blanco Fernando F FF Preet Ranjan R Aguado Andrea A Vishwakarma Vikalp V Stevens Laura E LE Vyas Alok A Padhye Subhash S Xu Liang L Weir Scott J SJ Anant Shrikant S Meisner-Kober Nicole N Brody Jonathan R JR Dixon Dan A DA

Oncotarget 20161101 45

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 t ...[more]

PMID: 27677075

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Dataset Information

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

Publications

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

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