A green tea component suppresses posttranslational expression of basic fibroblast growth factor in colorectal cancer.
OBJECTIVE
Green tea catechins are known to have anticarcinogenic effects. Epigallocatechin-3-gallate (EGCG) accounts for almost 50% of the total catechin content in green tea extract and has very potent antioxidant effects. EGCG also inhibits angiogenesis, possibly through the inhibition of proangiogenic factors including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which in turn, inhibits tumor growth and metastasis. However, the exact molecular mechanism by which EGCG suppresses bFGF expression is not known. Our objective was to elucidate the molecular mechanisms by which EGCG inhibits bFGF expression in colorectal cancer.


METHODS
We examined posttranslational regulation of bFGF by EGCG in human colorectal cancer cells. We also examined bFGF in intestinal tumor formation of APC(Min/+) mice with and without catechin treatment.


RESULTS
The bFGF protein was quickly degraded in the presence of EGCG, but a proteasome inhibitor suppressed this degradation. EGCG was also found to increase ubiquitination of bFGF and trypsin-like activity of the 20S proteasome, thereby resulting in the degradation of bFGF protein. Furthermore, EGCG suppressed tumor formation in APC(Min/+) mice, compared with vehicle-treated mice, in association with reduced bFGF expression.


CONCLUSIONS
The ubiquitin-proteasome degradation pathway contributes significantly to down-regulation of bFGF expression by EGCG. Catechin compounds have fewer adverse effects than chemotherapeutic agents and hence can be used as proof-of-concept in cancer therapeutics to suppress growth and metastasis by targeting proteins such as bFGF.
Laboratory of Environmental Carcinogenesis, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996, USA.
Mugdha
M
Sukhthankar
Kiyoshi
K
Yamaguchi
Seong-Ho
SH
Lee
Michael F
MF
McEntee
Thomas E
TE
Eling
Yukihiko
Y
Hara
Seung Joon
SJ
Baek
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D028241:Camellia sinensis / Q000737:chemistry; D002392:Catechin / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D003513:Cycloheximide / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D017491:Genes, APC; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
D000972:Antineoplastic Agents, Phytogenic; D015853:Cysteine Proteinase Inhibitors; D061988:Proteasome Inhibitors; D011500:Protein Synthesis Inhibitors; D016222:Fibroblast Growth Factor 2; C067713:lactacystin; D002392:Catechin; D003513:Cycloheximide; C045651:epigallocatechin gallate; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine