(-)-Epigallocatechin gallate suppresses the growth of human hepatocellular carcinoma cells by inhibiting activation of the vascular endothelial growth factor-vascular endothelial growth factor receptor axis.
The receptor tyrosine kinase vascular endothelial growth factor (VEGF) receptor (VEGFR) plays an important role in tumor angiogenesis of hepatocellular carcinoma (HCC). (-)-Epigallocatechin gallate (EGCG), the major biologically active component of green tea, inhibits growth in a variety of human cancer cells by inhibiting the activation of several types of receptor tyrosine kinases. In this study, we examined the effects of EGCG on the activity of the VEGF-VEGFR axis in human HCC cells. The levels of total and phosphorylated (i.e. activated) form of VEGFR-2 protein (p-VEGFR-2) were observed to increase in a series of human HCC cell lines in comparison to the Hc normal human hepatocytes. EGCG preferentially inhibited the growth of HuH7 HCC cells, which express constitutive activation of the VEGF-VEGFR axis, in comparison to Hc cells. Treatment of HuH7 cells with EGCG caused a time- and dose-dependent decrease in the expression of VEGFR-2 and p-VEGFR-2 proteins. The production of VEGF from HuH7 cells was reduced by treatment with EGCG. Drinking of EGCG significantly inhibited the growth of HuH7 xenografts in nude mice and this was associated with inhibition of the activation of VEGFR-2 and its related downstream signaling molecules, including ERK and Akt. EGCG drinking also decreased the expression of Bcl-x(L) protein and VEGF mRNA in the xenografts. These findings suggest that EGCG can exert, at least in part, its growth-inhibitive effect on HCC cells by inhibiting the VEGF-VEGFR axis. EGCG might therefore be useful in the treatment of HCC.
Shirakami
Yohei
Y
Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
Shimizu
Masahito
M
Adachi
Seiji
S
Sakai
Hiroyasu
H
Nakagawa
Takayuki
T
Yasuda
Yoichi
Y
Tsurumi
Hisashi
H
Hara
Yukihiko
Y
Moriwaki
Hisataka
H
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000096:biosynthesis / Q000187:drug effects
D016588:Anticarcinogenic Agents; D042461:Vascular Endothelial Growth Factor A; D051020:bcl-X Protein; D002392:Catechin; C045651:epigallocatechin gallate; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases