Gastric Carcinogenesis Inhibits 1 β and α Antisense Targeting Protein Kinase C Updated

Protein kinase C (PKC) family, which functions through serine/threonine kinase activity, is involved in signal transduction pathways necessary for cell proliferation, differentiation, and apoptosis. Its critical role in neoplastic transformation and tumor invasion renders PKC a potential target for anticancer therapy. In this study, we investigated the effect of targeting individual PKCs on gastric carcinogenesis. We established gastric cancer cell lines stably expressing antisense PKC , PKC 1, and PKC 2 cDNA. These stable transfectants were characterized by cell morphology, cell growth, apoptosis, and tumorigenicity in vitro and in vivo. PKC -AS and PKC 1-AS transfectants showed a different morphology with flattened, long processes and decreased nuclear:cytoplasmic ratio compared with the control cells. Cell growth was markedly inhibited in PKC -AS and PKC 1-AS transfectants. PKC -AS and PKC 1-AS cells were more responsive to mitomycin Cor 5-fluorouracil-induced apoptosis. However, antisense targeting of PKC 2 did not have any significant effect on cell morphology, cell growth, or apoptosis. Furthermore, antisense inhibition of PKC and PKC 1 markedly suppressed colony-forming efficiency in soft agar and in nude mice xenografts. Inhibition of PKC or PKC 1 significantly suppressed transcriptional and DNA binding activity of activator protein in gastric cancer cells, suggesting that PKC or PKC 1 exerts their effects on cell growth through regulation of activator protein activity. These data provide evidence that targeting PKC and PKC 1 by antisense method is a promising therapy for gastric cancer.