Hypoglycemia-induced VEGF expression is mediated by intracellular Ca2+ and protein kinase C signaling pathway in HepG2 human hepatoblastoma cells.
Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that plays a central role in angiogenesis. In this study, we investigated the mechanism of VEGF expression in HepG2 human hepatoblastoma cells under hypoglycemia. The shortage of glucose significantly enhanced VEGF mRNA expression in a time-dependent manner as well as increased DNA-binding activity of AP-1 that plays an important role in VEGF transcription. In addition, treatment of a potent PKC inhibitor, H-7 in glucose-deprived HepG2 cells suppressed hypoglycemia-elevated VEGF expression as well as the increased AP-1 DNA-binding activity. Moreover, we observed that Ca2+ levels remarkably increased under low glucose condition. Consistently, an intracellular Ca2+ chelator, BAPTA/AM significantly decreased hypoglycemia-induced VEGF expression and AP-1 DNA-binding activity. Therefore, these results indicate that increase of intracellular Ca2+ level induces the activation of PKC, which induce the activation of AP-1 leading to the increase of VEGF in glucose-deprived environment. Furthermore, it provides one link in regulation of VEGF with hypoglycemia as well as information to understand how hypoglycemia induces VEGF expression and subsequently leads to tumor angiogenesis.
Park
S H
SH
Department of Molecular Biology, Pusan National University, Pusan 609-735, Korea.
Kim
K W
KW
Lee
Y S
YS
Baek
J H
JH
Kim
M S
MS
Lee
Y M
YM
Lee
M S
MS
Kim
Y J
YJ
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D008222:Lymphokines / Q000235:genetics*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D008222:Lymphokines; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D005947:Glucose; D002118:Calcium