PTEN/Akt signaling through epidermal growth factor receptor is prerequisite for angiogenesis by hepatocellular carcinoma cells that is susceptible to inhibition by gefitinib.
Hepatocellular carcinoma (HCC) is one of the most common tumor-related causes of death worldwide for which there is still no satisfactory treatment. We previously reported the antiangiogenic effect of gefitinib, a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has been used successfully to treat lung cancer. In this study, we investigated the effects of gefitinib on tumor-induced angiogenesis by using HCC cell lines (HCC3, CBO12C3, and AD3) in vitro as well as in vivo. Oral administration of gefitinib inhibited angiogenesis induced by HCC3 and CBO12C3, but not by AD3 in the mouse dorsal air sac model. Production of both vascular endothelial growth factor (VEGF) and chemokine C-X-C motif ligand 1 (CXCL1) by EGF-stimulated HCC was more markedly inhibited by gefitinib in HCC3 and CBO12C3 cells than in AD3 cells. EGF stimulated the phosphorylation of EGFR, Akt, and extracellular signal-regulated kinase 1/2 (ERK1/2) in HCC3 and CBO12C3 cells, whereas EGF stimulated phosphorylation of EGFR and ERK1/2, but not Akt in AD3 cells. In fact, Akt was constitutively activated in the absence of EGF in AD3 cells. Gefitinib inhibited Akt phosphorylation in all three cell lines, but it was about five times less effective in AD3 cells. The concentration of PTEN in AD3 cells was about a half that in HCC3 and CBO12C3 cells. Transfection of HCC3 cells with PTEN small interfering RNA reduced their sensitivity to gefitinib in terms of its inhibitory effect on both Akt phosphorylation and the production of VEGF and CXCL1. In conclusion, effect of gefitinib on HCC-induced angiogenesis depends on its inhibition of the production of angiogenic factors, probably involving a PTEN/Akt signaling pathway.
Ueda
Shu-Ichi
S
Department of Medical Biochemistry, Graduate School of Medical Science and Station-II for Collaborative Research, Kyushu University, Fukuoka, Japan.
Basaki
Yuji
Y
Yoshie
Masumi
M
Ogawa
Katsuhiro
K
Sakisaka
Shotaro
S
Kuwano
Michihiko
M
Ono
Mayumi
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000096:biosynthesis; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000077156:Gefitinib; D018628:Gene Dosage; D018773:Genes, erbB-1; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008114:Liver Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D000970:Antineoplastic Agents; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D000077156:Gefitinib