Antisense targeting protein kinase C alpha and beta(1) inhibits gastric carcinogenesis

作者:Jiang XH; Tu SP; Cui JT; Lin MCM; Xia HHX; Wong WM; Chan AOO; Yuen MF; Jiang SH; Lam SK; Kung HF; Soh JW; Weinstein IB; Wong BCY*
来源:Cancer Research, 2004, 64(16): 5787-5794.
DOI:10.1158/0008-5472.CAN-03-1172

摘要

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 PKCalpha, PKCbeta(1), and PKCbeta(2) cDNA. These stable transfectants were characterized by cell morphology, cell growth, apoptosis, and tumorigenicity in vitro and in vivo. PKCalpha-AS and PKCbeta(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 PKCalpha-AS and PKCbeta(1)-AS transfectants. PKCalpha-AS and PKCbeta(1)-AS cells were more responsive to mitomycin C- or 5-fluorouracil-induced apoptosis. However, antisense targeting of PKCbeta(2) did not have any significant effect on cell morphology, cell growth, or apoptosis. Furthermore, antisense inhibition of PKCalpha and PKCbeta(1) markedly suppressed colony-forming efficiency in soft agar and in nude mice xenografts. Inhibition of PKCalpha or PKCbeta(1) significantly suppressed transcriptional and DNA binding activity of activator protein in gastric cancer cells, suggesting that PKCalpha or PKCbeta(1) exerts their effects on cell growth through regulation of activator protein activity. These data provide evidence that targeting PKCalpha and PKCbeta(1) by antisense method is a promising therapy for gastric cancer.

  • 出版日期2004-8-15
  • 单位上海市闵行区中心医院; 香港大学