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Antisense Targeting Protein Kinase C and ß₁ Inhibits Gastric Carcinogenesis

Department of ¹ Gastroenterology, Rui-jin Hospital, Shanghai, P.R. China; ² Department of Medicine and ³ Institute of Molecular Biology, University of Hong Kong, Hong Kong; and ⁴ Department of Medicine and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York

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, PKCß₁, and PKCß₂ cDNA. These stable transfectants were characterized by cell morphology, cell growth, apoptosis, and tumorigenicity in vitro and in vivo. PKC-AS and PKCß₁-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 PKCß₁-AS transfectants. PKC-AS and PKCß₁-AS cells were more responsive to mitomycin C- or 5-fluorouracil-induced apoptosis. However, antisense targeting of PKCß₂ did not have any significant effect on cell morphology, cell growth, or apoptosis. Furthermore, antisense inhibition of PKC and PKCß₁ markedly suppressed colony-forming efficiency in soft agar and in nude mice xenografts. Inhibition of PKC or PKCß₁ significantly suppressed transcriptional and DNA binding activity of activator protein in gastric cancer cells, suggesting that PKC or PKCß₁ exerts their effects on cell growth through regulation of activator protein activity. These data provide evidence that targeting PKC and PKCß₁ by antisense method is a promising therapy for gastric cancer.

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