Abstract |
Matrix metalloproteinase (MMP)-7 is considered to play essential roles in cancer progression. We examined the efficacy of auraptene, a citrus coumarin derivative, for suppressing MMP-7 expression in the human colorectal adenocarcinoma cell line HT-29. Auraptene remarkably inhibited the production of proMMP-7 protein, without affecting its mRNA expression level. Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), showed similar results, suggesting that auraptene suppresses mTOR-dependent proMMP-7 translation. Interestingly, however, auraptene showed no effects on the activation of Akt/mTOR signaling, whereas the phosphorylation levels of 4E binding protein (4EBP)1 and eukaryotic translation initiation factor (eIF)4B were substantially decreased. In addition, auraptene remarkably dephosphorylated constitutively activated extracellular signal-regulated kinase (ERK)1/2. Transfection of ERK1/2 siRNA led to a significant reduction of proMMP-7 protein production as well as of the phosphorylation of eIF4B. These results demonstrate that auraptene targets the translation step for proMMP-7 protein synthesis by disrupting ERK1/2-mediated phosphorylation of 4EBP1 and eIF4B.
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Authors | Kyuichi Kawabata, Akira Murakami, Hajime Ohigashi |
Journal | FEBS letters
(FEBS Lett)
Vol. 580
Issue 22
Pg. 5288-94
(Oct 02 2006)
ISSN: 0014-5793 [Print] England |
PMID | 16979634
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibiotics, Antineoplastic
- Coumarins
- Enzyme Precursors
- Eukaryotic Initiation Factors
- Neoplasm Proteins
- RNA, Messenger
- RNA, Small Interfering
- eIF-4B
- Protein Kinases
- MTOR protein, human
- TOR Serine-Threonine Kinases
- Metalloendopeptidases
- promatrilysin
- aurapten
- Sirolimus
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Topics |
- Antibiotics, Antineoplastic
(pharmacology)
- Cell Line, Tumor
- Citrus
(chemistry)
- Coumarins
(chemistry, pharmacology)
- Enzyme Precursors
(biosynthesis, genetics)
- Eukaryotic Initiation Factors
(metabolism)
- Humans
- MAP Kinase Signaling System
(drug effects)
- Metalloendopeptidases
(biosynthesis, genetics)
- Neoplasm Proteins
(biosynthesis, genetics)
- Phosphorylation
(drug effects)
- Protein Biosynthesis
(drug effects)
- Protein Kinases
(metabolism)
- Protein Processing, Post-Translational
(drug effects)
- RNA, Messenger
(biosynthesis, genetics)
- RNA, Small Interfering
(genetics)
- Sirolimus
(pharmacology)
- TOR Serine-Threonine Kinases
- Transfection
(methods)
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