• Molecules and Cells
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• v.38 no.11
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• pp.991-997
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• 2015

Tristetraprolin (TTP) is an AU-rich elements (AREs)-binding protein, which regulates the decay of ARE-scontaining mRNAs such as proto-oncogenes, anti-apoptotic genes and immune regulatory genes. Despite the low expression of TTP in various human cancers, the mechanism involving suppressed expression of TTP is not fully understood. Here, we demonstrate that Resveratrol (3,5,4'-trihydroxystilbene, Res), a naturally occurring compound, induces glioma cell apoptosis through activation of tristetraprolin (TTP). Res increased TTP expression in U87MG human glioma cells. Res-induced TTP destabilized the urokinase plasminogen activator and urokinase plasminogen activator receptor mRNAs by binding to the ARE regions containing the 3' untranslated regions of their mRNAs. Furthermore, TTP induced by Res suppressed cell growth and induced apoptosis in the human glioma cells. Because of its regulation of TTP expression, these findings suggest that the bioactive dietary compound Res can be used as a novel anti-cancer agent for the treatment of human malignant gliomas.

• Molecules and Cells
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• v.41 no.7
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• pp.653-664
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• 2018

The RNA-binding protein tristetraprolin (TTP) binds to adenosine-uridine AU-rich elements in the 3'-untranslated region of messenger RNAs and facilitates rapid degradation of the target mRNAs. Therefore, it regulates the expression of multiple cancer and immunity-associated transcripts. Furthermore, a lack of TTP in cancer cells influences cancer progression and predicts poor survival. Although the functions of TTP on cancer cells have previously been researched, the mechanism of TTP on the interaction between cancer cells with their micro-environment remains undiscovered. In this study, we admed to determine the role of cancer cell TTP during the interaction between tumor and immune cells, specifically regulatory T cells (Tregs). We evaluate the capability of TTP to modulate the antitumor immunity of GC and explored the underlying mechanism. The overexpression of TTP in GC cells dramatically increased peripheral blood mononuclear lymphocyte (PBML) -mediated cytotoxicity against GC cells. Increased cytotoxicity against TTP-overexpressed GC cells by PBMLs was determined by Treg development and infiltration. Surprisingly, we found the stabilization of programmed death-ligand 1 (PD-L1) mRNA was declining while TTP was elevated. The PD-L1 protein level was reduced in TTP-abundant GC cells. PD-L1 gas been found to play a pivotal role in Treg development and functional maintenance in immune system. Taken together, our results suggest the overexpression of TTP in GC cells not only affects cell survival and apoptosis but also increases PBMLs -mediated cytotoxicity against GC cells to decelerate tumor progression. Moreover, we identified PD-L1 as a critical TTP-regulated factor that contributes to inhibiting antitumor immunity.

• Journal of Microbiology and Biotechnology
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• v.24 no.2
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• pp.287-294
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• 2014

The transcription factor E2F1 is active during G1 to S transition and is involved in the cell cycle and progression. A recent study reported that increased E2F1 is associated with DNA damage and tumor development in several tissues using transgenic models. Here, we show that E2F1 expression is regulated by tristetraprolin (TTP) in prostate cancer. Overexpression of TTP decreased the stability of E2F1 mRNA and the expression level of E2F1. In contrast, inhibition of TTP using siRNA increased the E2F1 expression. E2F1 mRNA contains three AREs within the 3'UTR, and TTP destabilized a luciferase mRNA that contained the E2F1 mRNA 3'UTR. Analyses of point mutants of the E2F1 mRNA 3'UTR demonstrated that ARE2 was mostly responsible for the TTP-mediated destabilization of E2F1 mRNA. RNA EMSA revealed that TTP binds directly to the E2F1 mRNA 3'UTR of ARE2. Moreover, treatment with siRNA against TTP increased the proliferation of PC3 human prostate cancer cells. Taken together, these results demonstrate that E2F1 mRNA is a physiological target of TTP and suggests that TTP controls proliferation as well as migration and invasion through the regulation of E2F1 mRNA stability.

• Molecules and Cells
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• v.38 no.2
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• pp.156-162
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• 2015

Urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR) play a major role in the infiltrative growth of glioblastoma. Downregulatoion of the uPA and uPAR has been reported to inhibit the growth glioblastoma. Here, we demonstrate that tristetraprolin (TTP) inhibits the growth of U87MG human glioma cells through downregulation of uPA and uPAR. Our results show that expression level of TTP is inversely correlated with those of uPA and uPAR in human glioma cells and tissues. TTP binds to the AU-rich elements within the 3' untranslated regions of uPA and uPAR and overexpression of TTP decreased the expression of uPA and uPAR through enhancing the degradation of their mRNAs. In addition, overexpression of TTP inhibited the growth and invasion of U87MG cells. Our findings implicate that TTP can be used as a promising therapeutic target to treat human glioma.