PMID- 18053806
OWN - NLM
STAT- MEDLINE
DCOM- 20080205
LR  - 20220330
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 366
IP  - 1
DP  - 2008 Feb 1
TI  - A citrus polymethoxyflavonoid, nobiletin, is a novel MEK inhibitor that exhibits 
      antitumor metastasis in human fibrosarcoma HT-1080 cells.
PG  - 168-73
AB  - The activation of mitogen-activated protein/extracellular signal-regulated kinase 
      (MEK) is well known to be associated with tumor invasion and metastasis. We 
      previously reported that a polymethoxyflavonoid, nobiletin 
      (5,6,7,8,3',4'-hexamethoxyflavone), derived from Citrus depressa (Hayata), 
      inhibits the phosphorylation of MEK and thereby suppresses matrix 
      metalloproteinase (MMP) expression in a tumor-metastasis stimulator, 
      12-O-tetradecanoyl phorbol 13-acetate (TPA)-stimulated human fibrosarcoma HT-1080 
      cells [Mol. Cancer Ther. 3 (2004) 839-847]. In the present study, we investigated 
      whether or not nobiletin might directly influence MEK activity to exhibit the 
      antitumor metastatic activity in vitro. MEK kinase assay using myelin basic 
      protein (MBP) revealed that TPA-augmented MEK activity in HT-1080 cells and that 
      the augmented MEK activity was diminished by nobiletin treatment. In addition, 
      the decrease in MEK activity caused by nobiletin was found to inhibit the 
      phosphorylation of extracellular regulated kinases (ERK), a downstream signaling 
      factor for MEK. Furthermore, when an immunoprecipitated active MEK was incubated 
      with nobiletin under cell-free conditions, nobiletin was found to inhibit the 
      MEK-mediated MBP phosphorylation. In contrast, other citrus polymethoxyflavonoids 
      such as 3-hydroxy-5,6,7,8,3',4'-hexamethoxyflavone (natsudaidain) and 
      3,5,6,7,8,3',4'-heptamethoxyflavone, did not directly inhibit MEK activity. 
      Moreover, natsudaidain and 3,5,6,7,8,3',4'-heptamethoxyflavone exhibited no or 
      less inhibitory effect than nobiletin on the proMMP-9/progelatinase B production 
      in HT-1080 cells. Therefore, these results provide novel evidence that nobiletin 
      directly inhibits MEK activity and decreases the sequential phosphorylation of 
      ERK, exhibiting the antitumor metastatic activity by suppressing MMP expression 
      in HT-1080 cells.
FAU - Miyata, Yoshiki
AU  - Miyata Y
AD  - Department of Biochemistry and Molecular Biology, School of Pharmacy, Tokyo 
      University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 
      192-0392, Japan.
FAU - Sato, Takashi
AU  - Sato T
FAU - Imada, Keisuke
AU  - Imada K
FAU - Dobashi, Akira
AU  - Dobashi A
FAU - Yano, Masamichi
AU  - Yano M
FAU - Ito, Akira
AU  - Ito A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20071129
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Flavones)
RN  - 0 (Plant Extracts)
RN  - D65ILJ7WLY (nobiletin)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Antineoplastic Agents/*administration & dosage
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Citrus/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Activation/drug effects
MH  - Fibrosarcoma/*metabolism/pathology/*secondary
MH  - Flavones/*administration & dosage
MH  - Humans
MH  - Mitogen-Activated Protein Kinases/*antagonists & inhibitors
MH  - Plant Extracts/administration & dosage
EDAT- 2007/12/07 09:00
MHDA- 2008/02/06 09:00
CRDT- 2007/12/07 09:00
PHST- 2007/11/08 00:00 [received]
PHST- 2007/11/20 00:00 [accepted]
PHST- 2007/12/07 09:00 [pubmed]
PHST- 2008/02/06 09:00 [medline]
PHST- 2007/12/07 09:00 [entrez]
AID - S0006-291X(07)02532-6 [pii]
AID - 10.1016/j.bbrc.2007.11.100 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2008 Feb 1;366(1):168-73. doi: 
      10.1016/j.bbrc.2007.11.100. Epub 2007 Nov 29.