Citrus auraptene targets translation of MMP-7 (matrilysin) via ERK1/2-dependent and mTOR-independent mechanism.

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.

• 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)

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

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)