Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has attracted attention as a potential candidate for cancer therapy. However, many primary cancers are resistant to TRAIL, even when combined with standard chemotherapy. The mechanism of TRAIL resistance in cancer cells has not been fully elucidated. The TRAIL death receptor (DR) 3′-untranslated region (3′-UTR) is reported to contain AU-rich elements (AREs) that are important for regulating DR mRNA stability. However, the mechanisms by which DR mRNA stability is determined by its 3′-UTR are unknown. We demonstrate that tristetraprolin (TTP), an ARE-binding protein, has a critical function of regulating DR mRNA stability. DR4 mRNA contains three AREs and DR5 mRNA contains four AREs in 3′-UTR. TTP bound to all three AREs in DR4 and ARE3 in DR5 and enhanced decay of DR4/5 mRNA. TTP overexpression in colon cancer cells changed the TRAIL-sensitive cancer cells to TRAIL-resistant cells, and down-regulation of TTP increased TRAIL sensitivity via DR4/5 expression. Therefore, this study provides a molecular mechanism for enhanced levels of TRAIL DRs in cancer cells and a biological basis for posttranscriptional modification of TRAIL DRs. In addition, TTP status might be a biomarker for predicting TRAIL response when a TRAIL-based treatment is used for cancer.
Highlights
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which was independently identified in both 1995 and 1996 and is known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily [1,2]
The outcomes of numerous clinical trials have failed to achieve beneficial anticancer activity because many primary cancers are resistant to TRAIL, even when combined with the standard chemotherapy [3,4]
We found that DR4/5 contains multiple copies of AU-rich elements (AREs) in its 30 -UTR and investigated for the first time the role of TTP in posttranscriptional regulation of TRAIL DR4/5 gene expression in human colon cancer cells
Summary
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which was independently identified in both 1995 and 1996 and is known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily [1,2]. By binding to death receptor (DR) 4 or DR5, TRAIL induces tumor cell apoptosis without causing toxicity in normal cells. The stability of ARE-containing mRNAs is regulated by numerous ARE-binding proteins. Since its discovery as a regulator of tumor necrosis factor mRNA stability more than 20 years ago, TTP has become notable for its mediation of multiple cancers and immunity-associated transcripts. We found that DR4/5 contains multiple copies of AREs in its 30 -UTR and investigated for the first time the role of TTP in posttranscriptional regulation of TRAIL DR4/5 gene expression in human colon cancer cells. These results establish DR4/5 mRNA as a physiologic target of TTP and suggest that TTP regulation by DR4/5 transcript stability may be a key biomarker for the expression of DR4/5 observed in human cancers
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