title: Protein kinase C lies on the signaling pathway for vascular endothelial growth factor-mediated tumor development and angiogenesis.
abstract: The growth of any solid tumor depends on angiogenesis. Among the known angiogenic factors, vascular endothelial growth factor (VEGF) has been shown to play a pivotal role in tumor angiogenesis. However, to date, the signal transduction pathway initiated by VEGF is still not fully understood. It has been suggested that protein kinase C (PKC) plays an important role in the VEGF-induced signal transduction pathway in vitro, although the role of PKC in tumor angiogenesis in vivo still remains to be elucidated. By delivering the VEGF gene within the self-contained tetracycline-regulated retroviral vector (Retro-Tet) into hepatocellular carcinoma (HCC) cells, we manipulated VEGF expression by providing tetracycline in the drinking water to assess the tumor kinetics mediated exclusively by VEGF. In this study, we combined this Retro-tet system and LY333531, an inhibitor of the PKC-beta isoform, to elucidate the role of PKC-beta in tumor development and angiogenesis. Using a syngenic xenograft model, tumor augmentation induced by VEGF overexpression in HCC was markedly suppressed by oral administration of the PKC-beta inhibitor, with an accompanying reduction of neovascularization and p44/42 mitogen-activated protein kinase activation. This inhibitory effect was achieved even after the tumor was fully established. Immunohistochemical analysis revealed that apoptosis increased markedly in the tumor upon PKC-beta inhibitor treatment, whereas tumor cell proliferation itself did not change. Furthermore, with orthotopical transplantation, PKC-beta inhibition suppressed HCC tumor development in the liver. These results suggest that PKC-beta lies on the signal transduction pathway by which VEGF augments development and angiogenesis not only at the initial stage but also after the tumor is fully established.
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Japan. yoshijih@naramed-u.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Yoshiji
authors.forename: S
authors.initials: S
authors.lastname: Kuriyama
authors.forename: D K
authors.initials: DK
authors.lastname: Ways
authors.forename: J
authors.initials: J
authors.lastname: Yoshii
authors.forename: Y
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: M
authors.initials: M
authors.lastname: Kawata
authors.forename: Y
authors.initials: Y
authors.lastname: Ikenaka
authors.forename: H
authors.initials: H
authors.lastname: Tsujinoue
authors.forename: T
authors.initials: T
authors.lastname: Nakatani
authors.forename: M
authors.initials: M
authors.lastname: Shibuya
authors.forename: H
authors.initials: H
authors.lastname: Fukui
mesh_terms: D000818:Animals; D017209:Apoptosis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division; D016228:Endothelial Growth Factors / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D008222:Lymphokines / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000209:etiology* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000209:etiology*; D011493:Protein Kinase C / Q000502:physiology*; D013752:Tetracycline / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D013752:Tetracycline