Directed antisense therapy confirms the role of protein kinase C-α in the tumorigenicity of pancreatic cancer

Academic Article

Abstract

  • Background. The level of expression of the alpha isoform of protein kinase C (PKC-α) has been shown to correlate inversely with the pathologic differentiation of human pancreatic cancers. Methods. We stably transfected a moderately differentiated pancreatic cell line (HPAC) to overexpress PKC-α and examined the survival rates compared with parent HPAC according to an orthotopic model. Next we used a PKC-α antisense oligonucleotide specifically to down-regulate this isoform in vitro and examine the effect of treatment in vivo again according to the orthotopic model. Results. Animals implanted with the overexpressing cell line had a mortality rate almost twice that of those implanted with the parent cell line (P <. 01). Treatment with antisense oligonucleotide in increasing concentrations down-regulated PKC-α mRNA by Northern blot analysis and reverse transcriptase-polymerase chain reaction. Animals treated with antisense oligonucleotide after orthotopic implantation of pancreatic cancer cells survived statistically longer than those treated with vehicle alone (P = .005). Treatment with a scrambled oligonucleotide also conferred a survival benefit compared with vehicle alone (P < .01). Conclusions. Tumorigenicity of pancreatic cancer is related directly to PKC-α expression in vivo as demonstrated by decreased survival when overexpressed. PKC-α expression can be down-regulated directly (antisense) and indirectly (scrambled) in vitro, which subsequently confers a dramatic survival benefit in vivo.
  • Published In

  • Surgery  Journal
  • Digital Object Identifier (doi)

    Author List

  • Denham DW; Franz MG; Denham W; Zervos EE; Gower J; Rosemurgy AS; Norman J; Matthews JB; Vickers SM
  • Start Page

  • 218
  • End Page

  • 224
  • Volume

  • 124
  • Issue

  • 2