RRC ID 42213
Author Jiang XH, Tu SP, Cui JT, Lin MC, Xia HH, Wong WM, Chan AO, Yuen MF, Jiang SH, Lam SK, Kung HF, Soh JW, Weinstein IB, Wong BC.
Title Antisense targeting protein kinase C alpha and beta1 inhibits gastric carcinogenesis.
Journal Cancer Res
Abstract 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, PKCbeta1, and PKCbeta2 cDNA. These stable transfectants were characterized by cell morphology, cell growth, apoptosis, and tumorigenicity in vitro and in vivo. PKCalpha-AS and PKCbeta1-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 PKCbeta1-AS transfectants. PKCalpha-AS and PKCbeta1-AS cells were more responsive to mitomycin C- or 5-fluorouracil-induced apoptosis. However, antisense targeting of PKCbeta2 did not have any significant effect on cell morphology, cell growth, or apoptosis. Furthermore, antisense inhibition of PKCalpha and PKCbeta1 markedly suppressed colony-forming efficiency in soft agar and in nude mice xenografts. Inhibition of PKCalpha or PKCbeta1 significantly suppressed transcriptional and DNA binding activity of activator protein in gastric cancer cells, suggesting that PKCalpha or PKCbeta1 exerts their effects on cell growth through regulation of activator protein activity. These data provide evidence that targeting PKCalpha and PKCbeta1 by antisense method is a promising therapy for gastric cancer.
Volume 64(16)
Pages 5787-94
Published 2004-8-15
DOI 10.1158/0008-5472.CAN-03-1172
PII 64/16/5787
PMID 15313921
MeSH Animals Apoptosis / drug effects Apoptosis / genetics Cell Adhesion / genetics Cell Division / genetics Cell Line, Tumor DNA, Antisense / administration & dosage* DNA, Antisense / genetics Female Humans Mice Mice, Inbred BALB C Mice, Nude Protein Kinase C / antagonists & inhibitors* Protein Kinase C / genetics Protein Kinase C beta Protein Kinase C-alpha Stomach Neoplasms / enzymology Stomach Neoplasms / genetics Stomach Neoplasms / pathology Stomach Neoplasms / therapy* Transcription Factor AP-1 / antagonists & inhibitors Transfection Xenograft Model Antitumor Assays
IF 9.727
Times Cited 51
Human and Animal Cells