Thymoquinone-Induced Tristetraprolin Inhibits Tumor Growth and Metastasis through Destabilization of MUC4 mRNA

Tristetraprolin (TTP), a well-characterized AU-rich element (ARE) binding protein, functions as a tumor suppressor gene. The purpose of this study was to investigate whether a bioactive substance derived from a natural medicinal plant affects the induction of TTP and to elucidate its mechanism. We e...

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Published in:International journal of molecular sciences 2019-05, Vol.20 (11), p.2614
Main Authors: Lee, Se-Ra, Mun, Jeong-Yeon, Jeong, Mi-So, Lee, Hyun-Hee, Roh, Yun-Gil, Kim, Won-Tae, Kim, Min-Hye, Heo, Jeonghoon, Choi, Yung Hyun, Kim, Su Jin, Cha, Hee-Jae, Jun, Mira, Leem, Sun-Hee
Format: Article
Language:English
Subjects:
ARE
binding protein
bioactive substance
Biocompatibility
Biological activity
Biomedical materials
Breast cancer
Cancer therapies
Cell adhesion & migration
Cell cycle
Cell proliferation
Chemotherapy
Colorectal cancer
Curcumin
Destabilization
Gene expression
Genes
Herbal medicine
Kinases
Medical prognosis
Medicine
Melanoma
Mesenchyme
Metastases
Metastasis
mRNA
MUC4
Pancreatic cancer
Proteins
Resveratrol
Stability
Studies
TTP
Tumor cells
Tumor suppressor genes
Tumors
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Summary:Tristetraprolin (TTP), a well-characterized AU-rich element (ARE) binding protein, functions as a tumor suppressor gene. The purpose of this study was to investigate whether a bioactive substance derived from a natural medicinal plant affects the induction of TTP and to elucidate its mechanism. We examined the effects of natural bioactive materials including Resveratrol (RSV), thymoquinone (TQ) and curcumin on the expression of TTP in cancer cell. TQ derived from a natural plant increased the expression levels of TTP mRNA and proteins in a dose-dependent manner in gastric and breast cancer cells. TQ-induced TTP increased the instability of MUC4 mRNA by direct binding of TTP to ARE in the 3'UTR of MUC4 mRNA. The induction of TTP by TQ also reduced the proliferation, migration and invasion of cancer cells. The expression of the epithelial-mesenchymal (EMT)-related genes, which were target genes of TTP, was also decreased by the TQ treatment. In the in vivo experiments using mouse melanoma cells, TQ-induced TTP inhibited metastasis of tumor cells. We have found that TQ-induced TTP might inhibit metastasis by reducing tumor cell migration and invasion through destabilization of MUC4 mRNA, which suggest the MUC4 as a novel target to TTP.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms20112614