Protein kinase C lies on the signaling pathway for vascular endothelial growth factor-mediated tumor development and angiogenesis

The growth of any solid tumor depends on angiogenesis, Among the known angi ogenic factors, vascular endothelial growth factor (VEGF) has been shown to play a pivotal role in tumor angiogenesis, However, to date, the signal tr ansduction pathway initiated by VEGF is still not fully understood. It has been suggested that protein kinase C (PKC) plays an important role in the V EGF-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 manipulate d VEGF expression by providing tetracycline in the drinking water to assess the tumor kinetics mediated exclusively by VEGF. In this study, we combine d 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, U sing a syngenic xenograft model, tumor augmentation induced by VEGF overexp ression in BCC was markedly suppressed by oral administration of the PKC-be ta 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 an alysis revealed that apoptosis increased markedly in the tumor upon PKC-bet a inhibitor treatment, whereas tumor cell proliferation itself did not chan ge. Furthermore, with orthotopical transplantation, PKC-beta inhibition sup pressed HCC tumor development in the liver. These results suggest that PKC- beta lies on the signal transduction pathway by which VEGF augments develop ment and angiogenesis not only at the initial stage but also after the tumo r is fully established.